CN105188701A

CN105188701A - Crystalline forms of 3-(imidazo[1,2-b] pyridazin-3-ylethynyl)-4-methyl-n-(4-[(4-methylpiperazin-1-yl) methyl]-3-(trifluoromethyl)phenyl)benzamide and its mono hydrochloride salt

Info

Publication number: CN105188701A
Application number: CN201380072027.5A
Authority: CN
Inventors: C.K.默里; L.W.罗扎马斯; J.J.沙伯; P.夏尔马
Original assignee: Ariad Gene Therapeutics Inc
Current assignee: Ariad Pharmaceuticals Inc; Ariad Gene Therapeutics Inc
Priority date: 2012-12-12
Filing date: 2013-12-12
Publication date: 2015-12-23
Also published as: MX2015007578A; US20150315194A1; MX2021002255A; CL2015001643A1; JP2016503010A; MX2021002253A; MX2021002254A; CN115043843A; WO2014093579A3; MX2021002257A; US11192896B2; MX2021002258A; US11384086B2; US20190169196A1; JP2018168191A; US10125136B2; JP2022037122A; US20210277012A1; MX2021002256A; US20210277010A1

Abstract

Novel crystalline forms of 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyi-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyljbenzamide free base and 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyi-N-{4-[(4-methyl piperazi n-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide mono hydrochloride, pharmaceutical compositions thereof and methods of their preparation and use are disclosed herein. The instant application is directed to novel crystalline forms of 3-(imidazo[1,2-b] pyridazin-3-ylethynyl)-4-methyi-N-{4-[(4-methylpiperazin-1-yl) methyl]-3-(trifluoromethyl}phenyl}benzamide and 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyi-N-{4-[(4-methylpiperazin-1 -yl)methyl]-3-(trifluoromethyl)phenyl}benzamide mono hydrochloride, compositions comprising such crystalline forms, and to methods of their preparation and use.

Description

3-(imidazo [1,2-B] pyridazine-3-ethyl-acetylene base)-4-methyl-N{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl } Benzoylamide and its crystal form of mono-hydrochloric salts

The cross reference of related application

This application claims the U.S. Provisional Patent Application serial number 61/736,543 of December in 2012 submission on the 12nd; The U.S. Provisional Patent Application serial number 61/737,007 of December in 2012 submission on the 13rd; And the priority of the U.S. Provisional Patent Application serial number 61/788,208 of submission on March 15th, 2013, described U.S. Provisional Patent Application by reference entirety is incorporated to herein.

Background

The application relates to 3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl } Benzoylamide and 3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl benzamide monohydrochloride novel crystalline form, comprise the compositions of this type of crystal form, and relate to their preparation and application.

3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl } Benzoylamide has chemical formula C ₂₉h ₂₇f ₃n ₆o, it corresponds to formula weight 532.56g/mol.Its chemical constitution shows below:

3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl } the CAS registration number of Benzoylamide is 943319-70-8.

3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl } benzamide monohydrochloride has chemical formula C ₂₉h ₂₈clF ₃n ₆o, it corresponds to formula weight 569.02g/mol.Its chemical constitution shows below:

3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl } the CAS registration number of benzamide monohydrochloride is 1114544-31-8.

3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl } Benzoylamide the U.S. adopt title (USAN) and international nonproprietary name (INN) be pool that replace Buddhist nun (ponatinib).Moor that substituting chemical name for Buddhist nun and comprise 3-(2-imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-[4-[(4-methyl isophthalic acid-piperazinyl) methyl]-3-(trifluoromethyl) phenyl] Benzoylamide and 3-[2-(imidazo [1,2-b] pyridazine-3-base) acetenyl]-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl } Benzoylamide.

3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl } benzamide monohydrochloride the U.S. adopt title (USAN) and international nonproprietary name (INN) be hydrochloric acid moor that replace Buddhist nun.Hydrochloric acid is moored that substituting chemical name for Buddhist nun and is comprised 3-(2-imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-[4-[(4-methyl isophthalic acid-piperazinyl) methyl]-3-(trifluoromethyl) phenyl]-benzamide hydrochloride salt (1: 1) and 3-[2-(imidazo [1,2-b] pyridazine-3-base) acetenyl]-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl } benzamide monohydrochloride.

Mooring that for Buddhist nun is many targeting tyrosine kinase inhibitor that one is applicable to treat chronic lymphocytic leukemia (CML) and Other diseases.It is a kind ofly be in being used for the treatment of in clinical development and suffer from the general BCR-ABL of micromolecule (pan-BCR-ABL) inhibitor previous tyrosine kinase inhibitor therapy to chronic phase, accelerated period or the outbreak period CML of resistance or intolerance or the adult patients of Philadelphia Chromosome Positive acute lymphoblastic leukemia (Ph+ALL) that hydrochloric acid moors that for Buddhist nun.Other tyrosine kinase inhibitor relevant to this type of CML or Ph+ALL therapy comprises (imatinib mesylate (imatinibmesylate)) and (nilotinib (nilotinib)) (both are all from NovartisAG), (Dasatinib (dasatinib)) (from BristolMyersSquibbCompany) and (bosutinib (bosutinib)) (from PfizerInc).Hydrochloric acid is moored that new drug application (NDA) for Buddhist nun and is submitted to U.S. FDA on July 30th, 2012.USFDA checks and approves NDA on 14th in December in 2012, and hydrochloric acid moors that for Buddhist nun in brand name sell under (mooring that for Buddhist nun).

In addition, hydrochloric acid is moored that and potential is clinically applicable to treat other disease or condition of illness of involving for Buddhist nun by suppressing other protein kinase.This type of kinases and their associated conditions or condition of illness in O ' Hare, T. etc., CancerCell, 16th volume, 5th phase, mention in 401-412 (2009) and WO2011/053938, described document and described patent are incorporated to herein by reference for all objects all accordingly.

Understand and moored that potential polymorphic forms for the active pharmaceutical ingredient (API) of Buddhist nun for Buddhist nun and hydrochloric acid be applicable to developing drugs as moored that.The manufacture of API may be caused inconsistent this is because do not understand existence or required concrete polymorphic forms in API, and therefore medication the possibility of result change between each crowd of API.In addition, importantly find that the potential polymorphic forms of API is to make to determine that form goes through the stability in elongated segment period for similar reason system.Once select concrete polymorphic forms for drug development, importantly can reproducibly prepare that polymorphic forms.Because impurity likely affects the performance of medicine, so also desirable is there is one for preparing API with high-purity, moor for Buddhist nun and hydrochloric acid the method that replaces Buddhist nun as moored that.

It is WO2007/075869 that open hydrochloric acid known to applicant moors that patent disclosure the earliest for the chemical constitution of Buddhist nun, it is also applicant (ARIADPharmaceuticals, Inc.) had, and be incorporated to by reference herein for all objects accordingly.The embodiment 16 of WO2007/075869 is stated and is obtained product in solid form: 533m/z (M+H).This quality corresponds to that free alkali for Buddhist nun of pool.Embodiment 16 also discusses that preparation for the mono-hydrochloric salts of Buddhist nun of pool.It is crystallization that embodiment 16 had not both specifically mentioned that gained hydrochloric acid moored that for Buddhist nun, does not also specify hydrochloric acid to moor that any specific crystal form for Buddhist nun.

The United States serial 11/644,849 being disclosed as US2007/0191376 is correspondence applications of WO2007/075869, and on February 14th, 2012 with U.S. Patent number 8,114,874 authorize, and described patent is incorporated to herein by reference for all objects accordingly.United States serial 13/357,745 is USSN11/644, the application that continues of 849, and it is also incorporated to herein for all objects accordingly by reference.

The hydrochloric acid of containing had by applicant moors that for Buddhist nun, and to the submission date of the application, other patent application disclosed comprises WO2011/053938 and WO2012/139027, is incorporated to by reference herein all accordingly both it for all objects.Similar WO2007/075869, WO2011/053938 or WO2012/139027 all do not specify hydrochloric acid to moor that any specific crystal form for Buddhist nun.

General introduction

Found at present to moor that to moor that for Buddhist nun and hydrochloric acid and all can some crystallization and other polymorphic forms exist for Buddhist nun, wherein some form is suitable for pharmaceutical preparation and develops.

In one aspect, the disclosure relates to that polymorph for Buddhist nun of pool.Moor that polymorph for Buddhist nun and be appointed as crystal form A, crystal form B, crystal form C, crystal form D, crystal form E, crystal form F, crystal form G, form H, crystalline form I, crystal form J and crystal form K in this article.

On the other hand, the disclosure relate to comprise treatment effective dose pool disclosed herein that for the polymorph of Buddhist nun and the pharmaceutical composition of the pharmaceutically acceptable carrier of at least one, vehicle or excipient.

On the other hand, the disclosure relates to hydrochloric acid and moors that substantially pure crystal form for Buddhist nun.Hydrochloric acid is moored that substantially pure crystal form for Buddhist nun and is appointed as crystal form A, crystal form B, crystal form C, crystal form D, crystal form E, crystal form F, crystal form G, form H, crystalline form I, crystal form J and crystal form K in this article.

On the other hand, the disclosure relates to the hydrochloric acid disclosed herein comprising treatment effective dose and moors that for the substantially pure crystal form of Buddhist nun and the pharmaceutical composition of the pharmaceutically acceptable carrier of at least one, vehicle or excipient.

On the other hand, the disclosure provides a kind of for that to contact with hydrochloric acid for Buddhist nun and prepares hydrochloric acid and moor the method that replaces the substantially pure crystal form of Buddhist nun by making pool.

On the other hand, the disclosure relate to a kind of by people's administering therapeutic effective dose pool disclosed herein that treat the disease that Profilin kinases is reacted of described people or the method for condition of illness for polymorph of Buddhist nun.In certain embodiments, disease or condition of illness are chronic lymphocytic leukemia (CML).

On the other hand, the disclosure relates to and a kind ofly treats the disease reacted to Profilin kinases of described people or the method for condition of illness by mooring that to the hydrochloric acid disclosed herein of people's administering therapeutic effective dose for substantially pure crystal form of Buddhist nun.In certain embodiments, when protein kinase be Bcr-Abl or its mutant form time, disease or condition of illness are chronic lymphocytic leukemia (CML) or Philadelphia Chromosome Positive acute lymphoblastic leukemia (Ph+ALL).

Accompanying drawing is sketched

The following drawings forms the part of this description, and is included to further illustrate some aspect of the present invention.One or more by with reference in these accompanying drawings, the detailed description in conjunction with the specific embodiments presented herein better understands the present invention.

Fig. 1 is that hydrochloric acid moors that general introduction of 11 kinds of solid forms for Buddhist nun, and described solid form is included in and is accredited as crystal form A herein to K, and finds and disclosed HCl polymorph and pseudopolymorph.

Fig. 2 is that discovery and the disclosed hydrochloric acid in this article identified in Fig. 1 moors the general introduction that replaces some solid form of Buddhist nun.The legend of Fig. 2 is as follows:

^ainitial substance: the form H Cl1 obtained by lyophilization or amorphous substance (Am).

^boccurrence rate: total occurrence rate is included in 2 interim 216 experiments (describing in this paper embodiment 1) carried out, for described experiment, humid analysis 39 samples or evaporation analyze mother solution in addition, thus provide the material of total 254 sign.For example, " (3,1.2%) " occurs 3 times in measuring at 254 times corresponding to described form, thus provides the percentage ratio of 1.2%.62 times (9%) in measuring for 254 times, products collection efficiency is too low so that can not identify solid form, or material is moistening.

^dam: amorphous form.

Fig. 3 is that two batches of hydrochloric acid moor that characteristic X-ray powder diffraction (XRPD) figure of crystal form A for Buddhist nun, wherein before DVS humidity cycle and obtain the data of each batch afterwards.Relative intensity (to count) shows on the vertical axis, and the number of degrees (2 θ) display on the horizontal axis.

Fig. 4 moors by hydrochloric acid characteristic X-ray powder diffraction (XRPD) figure that crystal form A for Buddhist nun obtains.Relative intensity (to count) shows on the vertical axis, and the number of degrees (2 θ) display on the horizontal axis.

Fig. 5 moors by hydrochloric acid the characteristic differential scanning calorimetry (DSC) that crystal form A for Buddhist nun obtains to scan.Heat flow [mW] shows on the vertical axis, and temperature (DEG C) display on the horizontal axis.

Fig. 6 moors by hydrochloric acid characteristic thermogravimetric analysis (TGA) that crystal form A for Buddhist nun obtains and scans with the thermogravimetric analysis (TGMS) of mass spectral analysis volatile matter.

Fig. 7 moors that by hydrochloric acid to replace the crystal form A of Buddhist nun in DMSO-d ₆in the hydrochloric acid that obtains at 300k moor that for the characteristic of Buddhist nun in solution ¹h-NMR spectrum (600MHz).Normalized intensity shows on the vertical axis, and chemical shift (ppm) display on the horizontal axis.

Fig. 8 moors that by hydrochloric acid to replace the crystal form A of Buddhist nun in DMSO-d ₆in the hydrochloric acid that obtains at 300k moor that for the characteristic of Buddhist nun in solution ¹⁹f-NMR spectrum (564MHz).Normalized intensity shows on the vertical axis, and chemical shift (ppm) display on the horizontal axis.

Fig. 9 moors that by hydrochloric acid to replace the crystal form A of Buddhist nun in DMSO-d ₆in the hydrochloric acid that obtains at 300k moor that for the characteristic of Buddhist nun in solution ¹³c-NMR spectrum (151MHz).Normalized intensity shows on the vertical axis, and chemical shift (ppm) display on the horizontal axis.

Figure 10 moors by hydrochloric acid the characteristic properties spectrogram that crystal form A for Buddhist nun obtains, and wherein top mass spectrum is the observation quality of crystal form A, and bottom mass spectrum is the daughter ion spectrum of the parent of the above display of crystal form A.Relative abundance shows on the vertical axis, and atomic weight (m/z) display on the horizontal axis.

Figure 11 is the characteristic Fragmentation figure that hydrochloric acid moors that replaces the crystal form A of Buddhist nun.Relative abundance shows on the vertical axis, and atomic weight (m/z) display on the horizontal axis.

Figure 12 display moors according to the hydrochloric acid being appointed as the data presented in the table of " hydrochloric acid moors that crystal data for Buddhist nun's crystal form A and structure refinement " herein the structure that replaces the crystal form A of Buddhist nun.Atom in this Figure 12 carrys out encoded colors according to atomic type: carbon, Lycoperdon polymorphum Vitt; Nitrogen, blue; Oxygen, red; Hydrogen, white; Fluorine, yellow; Chlorine, green.

Figure 13 moors by hydrochloric acid the characteristic FT-IR spectrum that crystal form A for Buddhist nun obtains.Percent transmission (%) shows on the vertical axis, and wave number (cm ^-1) display on the horizontal axis.

Figure 14 moors by hydrochloric acid the characteristic HPLC spectrum that crystal form A for Buddhist nun obtains.Absorbance unit shows on the vertical axis (mAU), and time (minute) display on the horizontal axis.

Figure 15 be compared to crystal form B (centre) and crystal form C (top) XRPD figure moor that characteristic X-ray powder diffraction (XRPD) figure obtained for the crystal form A (bottom) of Buddhist nun by hydrochloric acid.Relative intensity (to count) shows on the vertical axis, and the number of degrees (2 θ) display on the horizontal axis.

Figure 16 moors by hydrochloric acid the characteristic HPLC spectrum that crystal form B for Buddhist nun obtains.Absorbance unit shows on the vertical axis (mAU), and time (minute) display on the horizontal axis.

Figure 17 be scheme (bottom) compared to the XRPD of crystal form A moor by hydrochloric acid characteristic X-ray powder diffraction (XRPD) pattern (top) that crystal form C for Buddhist nun obtains.Relative intensity (to count) shows on the vertical axis, and the number of degrees (2 θ) display on the horizontal axis.

Figure 18 moors by hydrochloric acid the characteristic differential scanning calorimetry (DSC) that crystal form C for Buddhist nun obtains to scan.Heat flow [mW] shows on the vertical axis, and temperature (DEG C) display on the horizontal axis.

Figure 19 moors by hydrochloric acid the characteristic thermogravimetric analysis (TGA) that crystal form C for Buddhist nun obtains to scan.

Figure 20 moors by hydrochloric acid the characteristic TGMS Thermogram that crystal form C for Buddhist nun obtains.

Figure 21 moors by hydrochloric acid the characteristic HPLC spectrum that crystal form C for Buddhist nun obtains.Absorbance unit shows on the vertical axis (mAU), and time (minute) display on the horizontal axis.

Figure 22 be compared to some other crystal form in crystal form A and HCl3 classification XRPD figure moor by hydrochloric acid characteristic X-ray powder diffraction (XRPD) figure that crystal form D for Buddhist nun obtains.Relative intensity (to count) shows on the vertical axis, and the number of degrees (2 θ) display on the horizontal axis.

Figure 23 moors by hydrochloric acid the characteristic differential scanning calorimetry (DSC) that crystal form D for Buddhist nun obtains to scan.Heat flow [mW] shows on the vertical axis, and temperature (DEG C) display on the horizontal axis.

Figure 24 moors by hydrochloric acid the characteristic thermogravimetric analysis (TGA) that crystal form D for Buddhist nun obtains to scan.

Figure 25 moors by hydrochloric acid the characteristic FT-IR spectrum that crystal form D for Buddhist nun obtains.Percent transmission (%) shows on the vertical axis, and wave number (cm ^-1) display on the horizontal axis.Crystal form A initial substance is with red display, and crystal form D (PSM1) shows with blueness.

Figure 26 moors by hydrochloric acid the characteristic HPLC spectrum that crystal form D for Buddhist nun obtains.Absorbance unit shows on the vertical axis (mAU), and time (minute) display on the horizontal axis.

Figure 27 be compared to some other crystal form in crystal form A and HCl5 classification XRPD figure moor by hydrochloric acid characteristic X-ray powder diffraction (XRPD) figure that crystal form F for Buddhist nun obtains.Relative intensity (to count) shows on the vertical axis, and the number of degrees (2 θ) display on the horizontal axis.

Figure 28 display moors by hydrochloric acid two characteristic differential scanning calorimetries (DSC) scannings that crystal form F for Buddhist nun obtains.Top scanning is the DSC curve of VDS1.Bottom scan is the DSC curve of VDS2.Heat flow [mW] shows on the vertical axis, and temperature (DEG C) display on the horizontal axis.

Figure 29 moors by hydrochloric acid the characteristic that thermogravimetric analysis obtained for the crystal form F (VDS1) of Buddhist nun and SDTA (top) and TGMS (bottom) scan to superpose.

Figure 30 moors by hydrochloric acid the characteristic that thermogravimetric analysis (top) obtained for the crystal form F (VDS2) of Buddhist nun and TGMS (bottom) scan to superpose.

Figure 31 moors by hydrochloric acid the characteristic FT-IR spectrum that crystal form F for Buddhist nun obtains.Percent transmission (%) shows on the vertical axis, and wave number (cm ^-1) display on the horizontal axis.Crystal form A initial substance is with red display, and crystal form F (VDS1) shows with green.

Figure 32 moors by hydrochloric acid the characteristic FT-IR spectrum that crystal form F for Buddhist nun obtains.Percent transmission (%) shows on the vertical axis, and wave number (cm ^-1) display on the horizontal axis.Crystal form A initial substance is with purple display, and crystal form F (VDS2) is with red display.

Figure 33 moors that characteristic HPLC spectrum obtained for the crystal form F (VDS2) of Buddhist nun by hydrochloric acid.Absorbance unit shows on the vertical axis (mAU), and time (minute) display on the horizontal axis.

Figure 34 be compared to some other crystal form in crystal form A (bottom) and HCl6 classification XRPD figure moor by hydrochloric acid characteristic X-ray powder diffraction (XRPD) figure that form H for Buddhist nun obtains.Relative intensity (to count) shows on the vertical axis, and the number of degrees (2 θ) display on the horizontal axis.

Figure 35 display moors by hydrochloric acid two characteristic differential scanning calorimetries (DSC) scannings that form H for Buddhist nun obtains.Top scanning is the DSC curve of VDS3.Bottom scan is the DSC curve of VDS4.Heat flow [mW] shows on the vertical axis, and temperature (DEG C) display on the horizontal axis.

Figure 36 moors by hydrochloric acid the characteristic that thermogravimetric analysis (top) obtained for the form H (VDS3) of Buddhist nun and TGMS (bottom) scan to superpose.

Figure 37 moors by hydrochloric acid the characteristic that thermogravimetric analysis (top) obtained for the form H (VDS4) of Buddhist nun and TGMS (bottom) scan to superpose.

Figure 38 moors by hydrochloric acid the characteristic FT-IR spectrum that form H for Buddhist nun obtains.Percent transmission (%) shows on the vertical axis, and wave number (cm ^-1) display on the horizontal axis.Crystal form A initial substance is with purple display, and form H (VDS3) is with red display.

Figure 39 moors by hydrochloric acid the characteristic FT-IR spectrum that form H for Buddhist nun obtains.Percent transmission (%) shows on the vertical axis, and wave number (cm ^-1) display on the horizontal axis.Crystal form A initial substance is with purple display, and form H (VDS4) is with red display.

Figure 40 moors that characteristic HPLC spectrum obtained for the form H (VDS4) of Buddhist nun by hydrochloric acid.Absorbance unit shows on the vertical axis (mAU), and time (minute) display on the horizontal axis.

Figure 41 is the superposition of characteristic X-ray powder diffraction (XRPD) figure of each solid form identified in Fig. 1, and wherein vertical axis represents relative intensity (counting), and trunnion axis represents 2 θ (number of degrees).From the bottom of this figure to top, following solid form and solvent as follows: initial substance hydrochloric acid moors that for Buddhist nun (HCl1) (crystal form A), form H Cl2 (QSA12.1, solvent: water) (crystal form B), form H Cl2b (QSA21.1, solvent: water) (crystal form C), form H Cl3 class (GRP12.1, solvent: toluene) (crystal form D), mixture HCl1+HCl4 (GRP1.1, solvent: phenyl-hexafluoride) (crystal form E), form H Cl5 (VDS28.1, solvent: butyl acetate) (crystal form F), form H Cl5b (VDS28.2, after drying, solvent: butyl acetate) (crystal form G) and HCl6 class (VDS6.1, solvent: methanol) (form H).

Figure 42 shows following thing (from top to bottom, representative number image from left to right): HCl6 class (VDS6.1, vds0S0.0c:E1), form H Cl5 (VDS28.1, vds05.0c:B3), form H Cl5b (VDS28.2, vds05.1c:B6), mixture HCl1+HCl4 (GRP1.1, grp02.0c:A1), form H Cl3 class (GRP12.1, grp02.1c:L1), form H Cl2 (QSA12.1, and form H Cl2b (QSA21.1, qsa00.1c:J2) qsa00.1c:A2).

Figure 43 moors by hydrochloric acid characteristic X-ray powder diffraction (XRPD) figure that crystal form J for Buddhist nun obtains.Relative intensity (to count) shows on the vertical axis, and the number of degrees (2 θ) display on the horizontal axis.

Figure 44 moors by hydrochloric acid characteristic X-ray powder diffraction (XRPD) figure that crystal form K for Buddhist nun obtains.Relative intensity (to count) shows on the vertical axis, and the number of degrees (2 θ) display on the horizontal axis.

Figure 45 shows hydrochloric acid and moors that and moor that figure of characteristic XRPD for Buddhist nun's (top pattern) (solvent: 2 for crystal form A (bottom pattern) of Buddhist nun and amorphous hydrochloric acid, 2,2 trifluoroethanols), wherein vertical axis represents relative intensity (counting), and trunnion axis represents 2 θ (number of degrees).

Figure 46 is amorphous 3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl } characteristic differential scanning calorimetry (DSC) Thermogram of benzamide monohydrochloride.Observe peak value the strong endothermic event of 259.4 DEG C, described peak value corresponds to the fusing point of amorphous form.Vertical axis represents heat flow [mW], and trunnion axis represents temperature (DEG C).

Figure 47 moors that characteristic HPLC spectrum obtained for the form H (VDS4) of Buddhist nun by hydrochloric acid.Absorbance unit shows on the vertical axis (mAU), and time (minute) display on the horizontal axis.Absorbance unit shows on the vertical axis (mAU), and time (minute) display on the horizontal axis.

Figure 48 is that general introduction of tabular for the solid form of Buddhist nun of pool, and described solid form comprises and is accredited as crystal form A to the polymorph of J and pseudopolymorph.

Figure 49 is accredited as the tabular general introduction of crystal form A to that occurrence rate for Buddhist nun's polymorph and pseudopolymorph of pool of J, method for crystallising, physical form, heat absorption and purity.

Figure 50 shows that molecular structure determined by single-crystal X-ray analysis for Buddhist nun's free base form A (dehydrate) of pool and numbering plan.

Figure 51 shows the XRPD figure of that simulation for Buddhist nun's free base form A (dehydrate) of pool and experiment acquisition.

Figure 52 is scanned by that characteristic differential scanning calorimetry (DSC) obtained for the crystal form A (dehydrate) of Buddhist nun's free alkali of pool.Heat flow [mW] shows on the vertical axis, and temperature (DEG C) display on the horizontal axis.

Figure 53 is shown category-B and moors that molecular structure determined by single-crystal X-ray analysis for Buddhist nun/Isosorbide-5-Nitrae-diox (1: 1) solvate (crystal form B) and numbering plan.

Figure 54 is that category-B is moored that and schemed for simulation XRPD of Buddhist nun/Isosorbide-5-Nitrae-diox (1: 1) solvate (crystal form B).

Figure 55 is shown category-B and moors that molecular structure determined by single-crystal X-ray analysis for Buddhist nun/perfluor benzene (1: 1) solvate (crystal form B) and numbering plan.

Figure 56 is that category-B moors that for the simulation of Buddhist nun/perfluor benzene (1: 1) solvate (crystal form B) and XRPD figure testing acquisition.

Figure 57 shows crystal form B and moors that for Buddhist nun/2-methyl THF (1: 0.4) solvate (top pattern); Crystal form B moors that for Buddhist nun/Ketohexamethylene (1: 1) solvate (middle pattern); Scheme with the XRPD of crystal form A (bottom pattern).

Figure 58 moors that characteristic differential scanning calorimetry (DSC) obtained for Buddhist nun/cyclohexanone solvent compound (QSA7.1) by category-B 1: 1 to scan.Heat flow [mW] shows on the vertical axis, and temperature (DEG C) display on the horizontal axis.

Figure 59 is that category-B 1: 1 moors that superposition of characteristic for TGA and the SDTA Thermogram of Buddhist nun/cyclohexanone solvent compound (QSA7.1).

Figure 60 moors that characteristic differential scanning calorimetry (DSC) obtained for Buddhist nun/2-methyl THF solvate (GEN8.1) by category-B 1: 0.4 to scan.Heat flow [mW] shows on the vertical axis, and temperature (DEG C) display on the horizontal axis.

Figure 61 is that category-B 1: 0.4 moors that superposition of characteristic for TGA and the SDTA Thermogram of Buddhist nun/2-methyl THF solvate (GEN8.1).

Figure 62 is scanned by that characteristic differential scanning calorimetry (DSC) obtained for the low crystal form C of Buddhist nun (GEN3.1) of pool.Heat flow [mW] shows on the vertical axis, and temperature (DEG C) display on the horizontal axis.

Figure 63 is that superposition of characteristic for TGA and the SDTA Thermogram of the low crystal form C of Buddhist nun (GEN3.1) of pool.

Figure 64 shows that XRPD for the low crystal form C of Buddhist nun (GEN3.1) (top pattern) and crystal form A (bottom pattern) of pool to scheme.

Figure 65 is scanned by that characteristic differential scanning calorimetry (DSC) obtained for the crystal form D (GEN5.1R1) of Buddhist nun of pool.Heat flow [mW] shows on the vertical axis, and temperature (DEG C) display on the horizontal axis.

Figure 66 is that superposition of characteristic for TGA and the SDTA Thermogram of the crystal form D (GEN5.1R1) of Buddhist nun of pool.

Figure 67 shows the XRPD figure of that crystal form D (middle pattern) for Buddhist nun of pool and crystal form A (bottom pattern).Also show that XRPD for the category-B solvate of Buddhist nun and the mixture of crystal form D of pool and scheme (top pattern).

Figure 68 moors that characteristic differential scanning calorimetry (DSC) obtained for Buddhist nun/THF1: 1 solvate (GEN7.1) by E class to scan.Heat flow [mW] shows on the vertical axis, and temperature (DEG C) display on the horizontal axis.

Figure 69 is that E class moors that superposition of characteristic for TGA and the SDTA Thermogram of Buddhist nun/THF1: 1 solvate (GEN7.1).

Figure 70 shows E class and moors that for Buddhist nun/THF1: 1 solvate (GEN7.1) (top pattern); E class moors that for Buddhist nun/chloroform solvate (SLP3.1) (middle pattern); Scheme with the XRPD of crystal form A (bottom pattern).

Figure 71 is that superposition of characteristic for TGA and the SDTA Thermogram of Buddhist nun crystal form F (AS16.2) of pool.

Figure 72 is characteristic differential scanning calorimetry (DSC) scanning obtained by form H (VLD1, the solid from liquid storage drying).Heat flow [mW] shows on the vertical axis, and temperature (DEG C) display on the horizontal axis.

Figure 73 is the characteristic superposition of TGA and the SDTA Thermogram of form H (VLD1, the solid from liquid storage drying).

Figure 74 shows below a series of XRPD to scheme: Fig. 1 is form H (VLD2 tests, after 2 weeks and drying); Fig. 2 is form H (VLD1 tests, after 2 weeks and drying); Fig. 3 is form H (VLD1 tests, from the solid of liquid storage drying, after DVS); Fig. 4 is form H (VLD1, the solid from liquid storage drying); Fig. 5 is form H (VLD19); And base map is the XRPD of crystal form A.

Figure 75 be with the FT-IR spectra overlapping that crystal form A is obtained by the characteristic FT-IR spectrum moored that and obtain for the form H of Buddhist nun.Percent transmission (%) shows on the vertical axis, and wave number (cm ^-1) display on the horizontal axis.

Figure 76 be with the FT-IR spectra overlapping that crystal form A is obtained by the characteristic FT-IR spectrum moored that and obtain for the form H of Buddhist nun, for the region of wavelength 1750-600nm.Percent transmission (%) shows on the vertical axis, and wave number (cm ^-1) display on the horizontal axis.

Figure 77 is characteristic differential scanning calorimetry (DSC) scanning obtained crystalline form I (GEN9.1).Heat flow [mW] shows on the vertical axis, and temperature (DEG C) display on the horizontal axis.

Figure 78 is the characteristic superposition of TGA and the SDTA Thermogram of crystalline form I (GEN9.1).

Figure 79 shows that XRPD for Buddhist nun's crystalline form I (top pattern) and crystal form A (bottom pattern) of pool in an overlapping arrangement to scheme.

Figure 80 shows below the superposition of XRPD figure: Fig. 6 is the XRPD figure of crystal form A (VDS2, after stability study); Fig. 7 is the XRPD figure of crystal form J (VDS2); Fig. 8 is the XRPD figure of crystal form J (VDS10 of screening S10010A); And Fig. 9 is that another XRPD for Buddhist nun's crystal form A of pool to scheme.

Figure 81 display and the characteristic FT-IR spectrum obtained by crystal form J to the FT-IR spectra overlapping that crystal form A obtains.Percent transmission (%) shows on the vertical axis, and wave number (cm ^-1) display on the horizontal axis.

Figure 82 display and the characteristic FT-IR spectrum obtained by crystal form J to the FT-IR spectra overlapping that crystal form A obtains, for the region of wavelength 1750-600nm.Percent transmission (%) shows on the vertical axis, and wave number (cm ^-1) display on the horizontal axis.

Figure 83 display is to the superposition of following selected that XRPD result obtained for Buddhist nun's free base polymorph thing (from bottom to top) of pool: crystal form A (SM); Category-B (QSAS7.1); Crystal form C, low crystallization (GEN3.1); Crystal form D (GEN5.1); E class (SLP3.1); Crystal form F (SLP10.1); Crystal form G (AS19.1); Form H (VDL19.1); Crystalline form I, low crystallization (GEN9.1); With crystal form J, low crystallization (VDS10.1).

Figure 84 shows the superposition of the XRPD figure of free alkali initial substance, and wherein two patterns represent two batches of (F09-05575: bottom pattern; And F09-05576: top pattern)

Figure 85 is to that characteristic differential scanning calorimetry (DSC) scanning obtained for Buddhist nun's free alkali initial substance batch F09-05575 of pool.Heat flow [mW] shows on the vertical axis, and temperature (DEG C) display on the horizontal axis.

Figure 86 is to that characteristic differential scanning calorimetry (DSC) scanning obtained for Buddhist nun's free alkali initial substance batch F09-05576 of pool.Heat flow [mW] shows on the vertical axis, and temperature (DEG C) display on the horizontal axis.

Figure 87 is that superposition of characteristic for TGA and the SDTA Thermogram of Buddhist nun's free alkali initial substance batch F09-05575 of pool.

Figure 88 is that superposition of characteristic for TGA and the SDTA Thermogram of Buddhist nun's free alkali initial substance batch F09-05576 of pool.

Figure 89 is that general introduction of tabular for the physical stability of Buddhist nun's solid form of some pools.

Figure 90 is the tabular general introduction expanding the result of experiment in proportion of selected free alkali form.

Figure 91 is that general introduction of tabular for the various signs of Buddhist nun's free alkali form of pool produced again under 120mg scale.

Detailed Description Of The Invention

Find 3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl } Benzoylamide and 3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl } both benzamide monohydrochloride all can various solid-state crystal form obtain.

Term " crystal form " or " polymorphic forms " or " polymorph " are used interchangeably in this article, and that moors that being different from pool that moors that for the amorphous form of Buddhist nun or moor that and moor that crystal form for other form of Buddhist nun for Buddhist nun or hydrochloric acid for Buddhist nun or hydrochloric acid for Buddhist nun for Buddhist nun or hydrochloric acid to refer to pool, as by some physical property (as thermodynamic stability), physical parameter, x-ray structure, DSC and preparation method determined.

Although polymorphic typically refers to compound can crystallize into more than one different crystal kinds (have identical chemical constitution, physicochemical properties are very different), but term " pseudo-polymorphic " is applied to solvate and hydrated crystalline form usually.But for the purpose of this disclosure, both true polymorph and pseudopolymorph (i.e. hydrate and solvate form thereof) include in the scope of term " crystal form " and " polymorphic forms ".In addition, " amorphous " refers to unordered solid-state.

Should notice that the different samples of specific crystal form can have identical main XRPD peak, but XRPD figure change can be there is about secondary peaks.About XRPD, term " about " typically refers in 0.3 degree of 2 θ set-points when using about XRPD maximum (representing with the 2 θ number of degrees).Or when being considered by those of ordinary skill in the art, term " about " can refer to (under this and all scenario), and value drops on accepting in error criterion of meansigma methods.As used herein, term " separation " and " substantially pure " refer to the summation relative to other solid form existed in selected species, and the crystallization of about more than 50% moors that, and to moor that for Buddhist nun for Buddhist nun or hydrochloric acid be that the crystal form identified exists (as the method by this area is determined).

definition and abbreviation

Solvent abbreviations:

DCM dichloromethane

DMAN, N-dimethyl acetylamide

DMFN, dinethylformamide

DMSO dimethyl sulfoxine

TFE2,2,2-trifluoroethanol

THF oxolane

2-methyl THF2-methyltetrahydrofuran

EtOH ethanol

MeOH methanol

Other abridges (lexicographic order):

Am amorphous

API active pharmaceutical ingredient

AS anti-solvent

CI counter ion counterionsl gegenions

DSC differential scanning calorimetry

DVS dynamic vapor sorption

GRP is used for the identifier of grinding experiment

HPLC high performance liquid chromatography

HT-XRPD high flux X-ray powder diffraction

HR-XRPD high-resolution X-ray powder diffraction

The low crystalline material of LC

MS mass spectrography

PSM for cooling/identifier of evaporative crystallization experiment

SAS dissolubility is assessed

The mono-differential thermal analysis of SDTA

S solvent

SM initial substance

TGA thermogravimetric analysis

The thermogravimetric analysis of TGMS and mass spectrography coupling

VDL is used for the identifier of steam to diffusion experiment in liquid

VDS is for the identifier of steam to diffusion experiment on solid

XRPDX ray powder diffraction

analytical method

x-ray powder diffraction

AvantiumT2 high flux XRPD device is used to obtain XRPD figure.Plate is arranged on and is equipped with on the BrukerGADDS diffractometer of Hi-Star area detector.

Use Silver behenate (for long d spacing) and corundum (for short d spacing) corrected X RPD platform.

At room temperature use in the 2 θ regions of monochromatic CuKa radiation between 1.5 ° and 41.5 ° and carry out data collection, described region is the most differentiated part of XRPD figure.In two 2 θ scopes (1.5 °≤2 θ≤21.5 ° (for the first frame), and 19.5 °≤2 θ≤41.5 ° (for the second frame)), collect the diffraction pattern in each hole, wherein the open-assembly time of each frame is 90 seconds.Background deduction or graduation of curve shall not be applied to XRPD figure.The carrier mass used during XRPD analyzes be X-ray institute through, and only slightly affect background.

thermal analyses

Melting property is obtained by the DSC Thermogram recorded with heat flux DSC822e instrument (Mettler-ToledoGmbH, Switzerland).With a small pieces indium (m.p.=156.6 DEG C; Δ Hf=28.45J.g ^-1) correct the temperature of DSC822e and enthalpy.Sample is sealed in standard 40 μ l aluminum dish, with pin perforation, and at the rate of heat addition 10 DEG C of min in DSC ^-1under be heated to 300 DEG C from 25 DEG C.During measuring, dry N ₂gas is at flow velocity 50mlmin ^-1under for purifying DSC equipment.

Measured because solvent or water are from the mass loss caused by the loss of various crystal prototype by TGA/SDTA.In TGA/SDTA851e instrument (Mettler-ToledoGmbH, Switzerland), monitor example weight between the period of heating, produce weight to temperature curve.The temperature of TGA/SDTA851e is corrected with indium and aluminum.To seal in samples weighing to 100 μ l aluminum crucible.Sealer pin is bored a hole, and at the rate of heat addition 10 DEG C of min- ¹under in TGA, crucible is heated to 300 DEG C from 25 DEG C.Dry N ₂gas is used for purification.

The gas of separating out from TGA sample is analyzed by mass spectrograph OmnistarGSD301T2 (PfeifferVacuumGmbH, Germany).Aftermentioned mass spectrograph is a kind of quadrupole mass spectrometer of the scope inner analysis quality at 0-200amu.

digital image

Adopt by the PhilipsPCVC840KCCD photographing unit of AvantiumPhotoslider software control, automatically collect the porose digital picture of each orifice plate.

pressing

For compression verification, use AtlasPowerPressT25 (Specac).AtlasPowerT25 is a kind of assisted hydraulic machine of operation under reaching 25 tons.

hPLC analytical method

Use the Agilent1200SLHPLC system being equipped with UV and MS detector, follow the following condition presented and carry out HPLC analysis:

tubing string: WatersSunfireC18 (100 × 4.6mm; 3.5 μm).

Column temperature: 35 DEG C

Compound integrity is expressed as the peak area percent calculated by the area at each peak in chromatogram except ' injection peak ' and total peak area

The peak area percent of target compound is used as the instruction to the purity of component in sample.

i. the polymorphic forms that replaces Buddhist nun's mono-hydrochloric salts is moored

Analyzed by XRPD, find that hydrochloric acid moors total 11 kinds of polymorphic forms that replaces Buddhist nun.11 kinds of Novel polymorphic Form are referred to herein as separately: HCl1 (in this article also referred to as " crystal form A "), HCl2 (in this article also referred to as " crystal form B "), HCl2b (in this article also referred to as " crystal form C "), HCl3 class (in this article also referred to as " crystal form D "), HCl1+HCl4 mixture (in this article also referred to as " crystal form E "), HCl5 class or only HCl5 (in this article also referred to as " crystal form F "), HCl5b or HCl5 desolventizing compound (desolvate) (in this article also referred to as " crystal form G "), HCl6 class (in this article also referred to as " form H "), HCl6 desolventizing compound (in this article also referred to as " crystalline form I "), HCl7 (in this article also referred to as " crystal form J ") and HCl8 (in this article also referred to as " crystal form K ").Character or the source of these 11 kinds of polymorphic forms are instructed in Fig. 1.In addition, some feature of the polymorphic forms mentioned also is provided in Fig. 2.For example, crystal form A is designated as hydrochloric acid and moors the dehydrate that replaces Buddhist nun, and obtains with single crystal form in addition.

In general, hydrochloric acid is moored that crystal form for Buddhist nun and is moored that for Buddhist nun compared to amorphous hydrochloric acid and have the physical property (as high stability etc.) being conducive to business and preparing solid dosage forms.Crystallization hydrochloric acid is moored that and is moored that for Buddhist nun and amorphous hydrochloric acid and can be easy to moor that replace physical-chemical data (such as DSC, XRPD, thermal analyses) of the identical type of indivedual crystal forms of Buddhist nun to observe for distinguishing hydrochloric acid disclosed herein for the difference between Buddhist nun.

With reference to preceding method, now pay close attention to 3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl } polymorph of each discovery of benzamide monohydrochloride.

the feature of crystal form A (HCl1):

Dehydrate HCl1 (crystal form identical with initial substance) is the predominant crystalline found.Hydrochloric acid is moored that chemical constitution for Buddhist nun and is clearly determined by nuclear magnetic resonance spectrometry (NMR), mass spectroscopy (MS) and the combination of single-crystal X-ray crystallography, Fourier transform infrared (FT-IR) spectrographic method and ultraviolet (UV) spectrographic method undertaken by the authentication data from element and the analysis of chlorine root.It is anhydrous crystal HCl-1 solid form or crystal form A that hydrochloric acid moors that preferred solid form for Buddhist nun.

With reference to Fig. 3, analyze hydrochloric acid by X-ray powder diffraction (XRPD) and moor that sample for Buddhist nun ASI batches 110020 and CGAM batch of F08-06057.In every case, amalyzing substances before and after DVS humidity cycle.High flux XRPD diffractometer is used to obtain XRPD figure.At room temperature use monochromatic CuK _αradiation carries out data collection in 2 θ regions between 1.5 ° and 41.5 °, and described region is the most differentiated part of XRPD figure.In two 2 θ scopes (1.5 °≤2 θ≤21.5 ° (for the first frame), and 19.5 °≤2 θ≤41.5 ° (for the second frame)), collect the diffraction pattern in each hole, wherein the open-assembly time of each frame is 90 seconds.Background deduction or graduation of curve shall not be applied to XRPD figure.Fig. 3 shows the X-ray powder diffraction figure of these materials separately in HCl-1 solid form.This powder pattern is consistent with according to the powder pattern of simulating the single-crystal X-ray diffraction experiment of HCl-1 form.The XRPD data instruction HCl-1 solid form obtained before and after the experiment of DVS humidity cycle is maintained after humidity cycle.In the XRPD figure of the crystal form A in figure 3, show at least one or all following peaks with the 2 θ number of degrees: 5.9; 7.1; 10.0; 12.5; 16.4; 19.3; 21.8; 23.8; With 26.1.In certain embodiments, the XRPD figure of crystal form A shows two peaks, three peaks, four peaks or five peaks.Term " about " is applied to each listed peak of this and other forms all mentioned in the disclosure.

Fig. 4 shows hydrochloric acid and moors characteristic X-ray powder diffraction (XRPD) figure that replaces the crystal form A of Buddhist nun, wherein observes the more details relevant with XRPD.The XRPD figure of the crystal form A shown in Fig. 4 shows at least one or more following peak with the 2 θ number of degrees: 5.9; 7.1; 10.0; 12.5; 13.6; 14.1; 15.0; 16.4; 17.7; 18.6; 19.3; 20.4; 21.8; 22.3; 23.8; 24.9; 26.1; 27.0; 28.4; 30.3; 31.7; With 35.1.In certain embodiments, the feature of crystal form A is that XRPD figure comprises one or more following peak 2 θ: 12.5; 19.3; 23.8; With 26.1.In certain embodiments, the XRPD figure of crystal form A shows two peaks, three peaks, four peaks or five peaks.

In differential vapor sorption (DVS) experiment carried out with HCl-1, at constant temperature 25 DEG C, relative humidity is from 45% being circulated to 95% (absorption), to 0% (desorbing) and be back to 45% (absorption), and the retention time wherein often walked is 60 minutes.The result presentation that this DVS for Buddhist nun CGAM batch F08-060507 tests is moored to hydrochloric acid under 95% humidity, absorbs water 1.1%, and hydrochloric acid is moored that and is presented in relative humidity 95% time water suction 1.4% for Buddhist nun ASI batches 110020.Be circulated to comparatively low humidity time, this water suction is reversible.These results prove that HCl-1 is not hygroscopic compound.Also the impact of humidity cycle on HCl-1 is assessed by carrying out X-ray powder diffraction (XRPD) analysis before and after DVS experiment.XRPD data disclose humidity cycle on the solid form of material without impact, and it keeps in HCl-1 solid form.

With reference to Fig. 5, moor by differential scanning calorimetry (DSC) hydrochloric acid measured in HCl-1 solid form the fusing point that replaces Buddhist nun.Use dry N ₂gas purification, under the rate of heat addition of 10 DEG C per minute, in the temperature range of 25 DEG C to 300 DEG C, analyzes hydrochloric acid and moors that sample for Buddhist nun ASI batches 110020 in pin hole crucible.Observe peak value the strong endothermic event of 264.1 DEG C, described peak value corresponds to the fusing point of crystal form A.

With reference to Fig. 6, hydrochloric acid is moored that and carries out thermogravimetric analysis (TGA) and the thermogravimetric analysis (TGMS) with mass spectral analysis volatile matter for Buddhist nun ASI batches 110020.The sample contained in pin hole crucible is heated to 300 DEG C from 25 DEG C in TGA instrument under the rate of heat addition 10 DEG C of min-1, wherein dry N ₂gas is used for purification.Use the gas that quadrupole mass spectrometer analysis is separated out from TGA.Hydrochloric acid in HCl-1 solid form is moored that and is contained the water of 0.31 % by weight and the ethanol of 0.85 % by weight for Buddhist nun ASI batches 110020 when discharging.Mass loss 0.2% (water) and 0.6% (ethanol, from recrystallisation solvent) is observed in TGA/TGMS experiment instruction respectively between temperature range 25-130 DEG C and 130-240 DEG C.These losses are consistent with the water when discharging and ethanol content.Ethanol higher than the temperature of water from substance release, but does not moor to the hydrochloric acid as solvate in HCl-1 solid form that is relevant for Buddhist nun from the temperature of substance release.

Mooring that crystal form A for Buddhist nun to hydrochloric acid uses the extensive solution phase NMR research of the combination of multiple 1D and 2DNMR method right to obtain ¹h, ¹⁹f and ¹³the complete appointment of C resonance, and therefore confirm that hydrochloric acid moors the chemical constitution that replaces Buddhist nun.At ARIADPharmaceuticalsInc. (Cambridge, MA) to being dissolved in deuterate DMSO (DMSO-d ₆) hydrochloric acid in solvent moors that sample for Buddhist nun (ASI batch 110020) and analyze.On the BrukerAvanceIII-600MHzNMR spectrogrph being equipped with 5mmBBFOz-gradient probe, NMR spectrum is obtained at the temperature of 300K.All 1H chemical shifts are all with reference to the DMSO peak at 2.5ppm place.With reference to Fig. 7, display hydrochloric acid is moored that and is replaced the crystal form A of Buddhist nun in DMSO-d ₆in 1D ¹h-NMR spectrum. ¹h resonance 32a moors that by hydrochloric acid and causes for the protonated piperazine moiety in Buddhist nun.Appear at ¹h (Fig. 7) with ¹³etOH resonance in both C spectrum (Fig. 9) is moored that by hydrochloric acid and is caused for the remaining EtOH existed in Buddhist nun.Fig. 8 shows hydrochloric acid and moors that for the crystal form A of Buddhist nun in DMSO-d ₆in 1D ¹⁹f-NMR spectrum, wherein Characteristic chemical shifts is at 57.94ppm place.Fig. 9 shows hydrochloric acid and moors that for the crystal form A of Buddhist nun in DMSO-d ₆in 1D ¹³c-NMR spectrum.

Table 1 summarize pool that for Buddhist nun's mono-hydrochloric salts crystal form A from ¹h and ¹³the related chemistry displacement data that C-NMR experiment obtains.The number of signal and their relative intensity (integration) confirm that hydrochloric acid moors that number for the proton in the structure of the crystal form A of Buddhist nun and carbon.These chemical shift datas are reported according to the following atom numbering plan at once shown:

table 1: hydrochloric acid moors that for the crystal form A of Buddhist nun in DMSO-d at 300k ₆ in ¹ h and ¹³ c chemical shift data (in ppm).

Atom is numbered	Group	¹H，ppm	¹³C，ppm	Integration	¹H multiplicity, Hz	¹³C multiplicity, Hz
							3	CH	8.72	145.03	0.98	m ¹
4	CH	7.39	119.05	1.02	dd ²(J＝9.2，4.4)
							5	CH	8.25	126.06	ND ⁷	m
6	C	-	139.63	-	-
							8	CH	8.22	138.2	ND	m
9	C	-	111.69	-	-
							10	C	-	81.11	-	-
11	C	-	96.38	-	-
							12	C	-	121.76	-	-
13	C	-	143.52	-	-

14	CH	7.54	130.03	1.01	d ³(J＝8.1)
							15	CH	7.98	128.49	1.02	dd(J＝8，1.4)
16	C	-	132.12	-	-
							17	CH	8.22	130.19	ND	m
18	CH ₃	2.6	20.36	3.09	s ⁴
							19	C	-	164.63	-	-
21	NH	10.65	-	1.03	s
							22	C	-	138.53	-	-
23	CH	8.13	123.54	1.02	d(J＝8.4)
							24	CH	7.71	131.42	1.01	d(J＝8.4)
25	C	-	130.95	-	-
							26	C	-	127.53	-	-	q ⁶(J＝29.7)
27	CH	8.25	117.42	ND	m	q(J＝6.2)
							28	CH ₂	3.66	56.56	2.01	s	-
35	C	-	124.25	-	-	q(J＝272.9)
							37	CH ₃	2.74	41.96	3.07	s
30，34 ⁸	CH ₂	2.87	49.16	1.76	m
							30′，34′ ⁸	CH ₂	2.52	49.16	ND	m
31，33 ⁸	CH ₂	3.02	52.53	1.78	m
							31′，33′ ⁸	CH ₂	3.35	52.53	-	-
32a	NH	10.85	-	0.74	br.s. ⁵
							36，38，39	CF ₃	¹⁹F：-57.9	-	-	-

M: multiplet

Dd: double doublet

D: doublet

S: unimodal

Br.s: wide unimodal

Q: quartet

ND: due to ¹spectra overlapping in HNMR spectrum and not measuring.

Due to symmetry, resonate to 30 and 34 and resonance to 31 and 33, there is degeneration displacement study.In addition, the methene proton of these resonance occurs form with diastereo-isomerism.

With reference to Figure 10, use ThermoFinneganExactive accurate mass instrument and LTQXL ion trap mass spectrometer carry out hydrochloric acid moor that for the Mass spectrometry experiments of the crystal form A of Buddhist nun and the MS2 of collisional activation cracked, wherein said mass spectrograph operates with positive ionization electrospray pattern separately.The hydrochloric acid be dissolved in acetonitrile moored that sample for the crystal form A of Buddhist nun (ASI batch 110020) by syringe pump infusion to introduce in mass spectrograph.Exactive mass spectrograph uses full scan pattern obtain hydrochloric acid and moor the accurate mass that replaces Buddhist nun.The quality observed in the experiment of this infusion is m/z533.2269 (MH+), the accurate mass wherein calculated is 533.2271 (MH+), thus produces mass discrepancy 0.2mmu (Δ ppm-0.38) (Figure 10 top).Hydrochloric acid is moored that and is shown in Figure 10 for the cracked spectrum of Buddhist nun on Exactive mass spectrograph, and contains from the product ion (hydrochloric acid moors the molecular ion that replaces Buddhist nun) of m/z533.2269 and the ion from other co-elute compound any.

Figure 11 is presented at the cracked data of the MS that LTQXL ion trap mass spectrometer obtains.The full scan MSm/z533 (MH+) of sample during Figure 11 (A) is presented at infusion.The fragment spectrum of the selected quality m/z533 of Figure 11 (B) (MS2 scanning) display.Figure 11 (C) and Figure 11 (D) shows the product ion from m/z433 and 260 respectively; Ion m/z433 and 260 itself is the initial product ion (molecular ion) from m/z533.

Single-crystal X-ray diffraction analysis is for determining that hydrochloric acid moors the crystal structure that replaces the crystal form A of Buddhist nun.Use steam to diffusion crystallisation method in liquid, utilize hydrochloric acid to moor that and moor for the Buddhist nun CGAM batch of F08-06057 hydrochloric acid obtained in dehydrate HCl-1 form the monocrystal that replaces Buddhist nun.Use methanol as solvent by single-crystal X-ray diffraction analysis, the monocrystal obtained using ethyl acetate as anti-solvent.According to earlier experiments, the crystal diffraction of this form known is good, and cause the hydrochloric acid shown in Figure 12 to moor that parsing for the structure of Buddhist nun, wherein crystallographic parameters is summarized in table 2.Moor that to hydrochloric acid and analyzes consistent with previously described for NMR of Buddhist nun, the terminal nitrogen of piperazine is that hydrochloric acid is moored that and replaced protonated site in Buddhist nun.Chlorine counter ion counterionsl gegenions are closely adjacent to protonated site in crystal structure to be existed.Based on this structural analysis, determine that crystal form A is anhydrous form.

table 2: hydrochloric acid moors that crystal data for Buddhist nun's crystal form A and structure refinement.

Identification code	S11022
		F(000)	2368
Crystalline size [mm ³]	0.40×0.30×0.20
		For the θ scope [°] of data collection	3.2-32.5
The reflection number collected	29574
		Independently reflect number	10117[R _int＝0.0395]
The integrity degree [%] of 0=32.5 °	98.8
		Minimum and maximum transmission	0.9632 and 0.9283
Data/restriction/parameter	10117/0/473
		Based on F ²The goodness of fit	1.070
Final R index [1 > 2 σ (l)]	R1＝0.0644，wR2＝0.1501
		R index (all data)	R1＝0.0957，wR2＝0.1672

Hydrochloric acid is moored that attenuated total reflectance (ATR) FT-IR spectrum for the crystal form A of Buddhist nun ASI batches 110020 and is shown in Figure 13.Table 3 provides the hydrochloric acid based on the FT-IR shown in Figure 13 to moor that and replaces the general introduction that selected by Buddhist nun, IR bands of a spectrum are specified.

table 3: hydrochloric acid is moored those selected IR bands of a spectrum for Buddhist nun and specified

Absorption band	Frequency (cm ^-1)	Region in Figure 13
			C-H stretches (vCH3, vCH2)	2938.1(2870-2960)	A
N-H stretches	3242.1	A
			C=C stretches	2220.0	B
C=O stretches (amide 1)	1669.8	C
			N-H bends (amide 2)	1531.8	D
C-N stretches	1314.9	F
			C-F stretches	1122.6	H
Aromatics C-H out-of-plane bending	857.3，789.7	1

In FT-IR, functional group region extends to 1300cm-1 from 4000cm-1.In the region (region A) from 3300cm-1 to 2800cm-1, there is multiple overlap, absorption band is caused by the stretching vibration between hydrogen and other atom a certain, described flexible may be all be present in hydrochloric acid to moor that is flexible for the amide N-H in the structure of Buddhist nun, aromatics C-H flexible (from imidazo-pyridazine heterocycle and phenyl) and aliphatic C-H stretches (in methyl and methylene).Faint bands of a spectrum in 2100-2260cm-1 (region B) are because triple C-C key stretches.Can expect that moderate strength bands of a spectrum owing to amide C=O flexible (amide 1) are within the scope of 1640-1690cm-1, may be the bands of a spectrum observed under 1669.8cm-1 (region C).Secondary amide N-H bends the absorption band producing in the scope of 1500-1560cm-1 (amide 2), wherein observes two strong bands of a spectrum (region D).The multiple faint extremely medium bands of a spectrum observed in the scope of 1300-1600cm-1 are due to the two C-C of (mixing) aromatics resonance stabilization and two C-N key (ring stretching vibration) and C-H bending vibration (from methyl and methylene) (region E).Can expect that aromatics and aliphatic amine C-N stretch bands of a spectrum respectively in the scope of 1250-1335cm-1 and in the scope of 1250-1020cm-1, wherein observe multiple bands of a spectrum, be included in the strong especially bands of a spectrum (region F, G) at 1314.9cm-1 place.Finger print region 1300 to 910cm-1 is complicated, wherein has the strong broad band (region H) that possibility is stretched owing to C-F at 1122.6cm-1 place.Aromatic region 910 to 650cm-1 absorption band is mainly due to the out-of-plane bending of heteroaromatic rings c h bond, thus indication compound has heteroaromatic character (region I).These Data support hydrochloric acid in FT-IR spectrum moor the structure that crystal form A for Buddhist nun has proposition.

Carry out the experiment of the purity measuring crystal form A.With reference to Figure 14, it is 99.8160% (area percentage) that mensuration hydrochloric acid moors that purity for the crystal form A of Buddhist nun.

the feature of crystal form B (HCl2):

Obtain form H Cl2 by the dissolubility of assessment in TFE/ water, and it forms HCl2b measuring transforming one day after that plate stores at ambient conditions, as by the XRPD of concrete sample is measured again confirm.HCl2 also obtains from Aqueous solvent systems (water and MeOH/ water) in the 2 interim experiments carried out as herein described, and it transforms to form HCl2b (general introduction see in Fig. 2) after also storing at ambient conditions.

Crystal form B is analyzed by X-ray powder diffraction (XRPD).Figure 15 shows XRPD figure (from bottom to top) of following thing: initial substance (crystal form A), form H Cl2 (crystal form B) (QSA12.1, solvent: water) and form H Cl2b (crystal form C) (QSA12.2 measures after a couple of days at ambient conditions again).In the XRPD figure of the crystal form B in fig .15, show at least one or all following peaks with the 2 θ number of degrees: 3.1; 6.5; 12.4; 13.8; 15.4; 16.2; 17.4; 18.0; 20.4; 23.2; 24.4; 26.1; With 26.9.For supplying reference, in the XRPD figure of the crystal form C in fig .15, show at least one or all following peaks with the 2 θ number of degrees: 6.5; 12.4; 13.8; 17.4; 18.0; 20.6; 22.0; 23.0; 25.5; 26.5; With 27.4.In certain embodiments, the feature of crystal form B is that XRPD figure comprises one or more following peak 2 θ: 13.8; 15.4; 17.4; 18.0; 26.1; With 26.9.In these embodiments, the XRPD figure of crystal form B and C shows two peaks, three peaks, four peaks or five peaks.

Carry out the experiment of the purity measuring crystal form B.With reference to Figure 15, it is 99.7535% (area percentage) that mensuration hydrochloric acid moors that purity for the crystal form B of Buddhist nun.

the feature of crystal form C (HCl2b):

Crystal form C is a kind of hydrated form.Form H Cl2b assesses experiment by dissolubility at first, and the conversion being gone through many skies by crystal form B is at ambient conditions obtained, or directly obtains from TFE/ aqueous solvent mixture.Crystal form C also obtains (general introduction see in Fig. 2) from Aqueous solvent systems (Shui Heshui/DMSO) in the experiment of 2 phases.

Crystal form C is analyzed by X-ray powder diffraction (XRPD).Figure 17 shows XRPD figure (from bottom to top) of following thing: initial substance (HCl1) and form H Cl2b (QSA21.1, solvent: water).In the XRPD figure of the crystal form C in fig. 17, show at least one or all following peaks with the 2 θ number of degrees: 3.1; 6.5; 12.4; 13.8; 17.4; 18.0; 20.6; 22.0; 23.0; 25.5; 26.5; 27.4; 28.4; With 29.0.In certain embodiments, the feature of crystal form C is that XRPD figure comprises one or more following peak 2 θ: 13.8; 17.4; 18.0; With 25.5.In certain embodiments, the XRPD figure of crystal form C shows two peaks, three peaks, four peaks or five peaks.

With reference to Figure 18, measure hydrochloric acid by differential scanning calorimetry (DSC) and moor the fusing point that replaces the crystal form C of Buddhist nun.Use dry N ₂gas purification, under the rate of heat addition of 10 DEG C per minute, in the temperature range of 25 DEG C to 300 DEG C, analyzes sample in pin hole crucible.Strong endothermic event occurs in T _{peak value}=122.9 DEG C, T _{peak value}=158.2 DEG C and T _{peak value}=256.2 DEG C of places.

Figure 19 shows TGA and the SDTGA Thermogram of QSA21.1.The TGMS Thermogram of the crystal form C that Figure 20 display is obtained by experiment QSA21.1.Mass loss 4.3% (water) is observed in 40 DEG C-140 DEG C, temperature interval.API: water ratio estimation is 1: 1.4.

Carry out the experiment of the purity measuring crystal form C.With reference to Figure 21, it is 99.7850% (area percentage) that mensuration hydrochloric acid moors that purity for the crystal form C of Buddhist nun.

the feature of crystal form D (HCl3 class):

HCl3 class mainly obtains from arsol, and as can seen in general introduction in fig. 2, exception part be MeOH/ acetonitrile mixture.Be used in the cooling-evaporative crystallization success under 120mg scale carried out in toluene and produce crystal form D again.

Based on thermal analyses, the sample representing crystal form D is appointed as toluene solvant form (API: toluene 1: 0.5).The desolventizing at 199.5 DEG C of described form, recrystallization, and second melting is observed under 257.6 DEG C (most probable corresponds to the fusing point of crystal form A).HCl3 class has slight hygroscopicity, and wherein under 95%RH, water quality absorbs 2.5%.Described process is reversible about physical stability and sample appearance.

Find that HCl3 class sample stores 8 months at ambient conditions afterwards and have physical stability after DVS circulation.But in humidity chamber (40 DEG C/75%RH) after 1 week, HCl3 class sample changes into HCl1.

Crystal form D is analyzed by X-ray powder diffraction (XRPD).The XRPD that Figure 22 shows the XRPD superposition of following thing schemes (from bottom to top): HCl1 (AP24534 hydrochlorate initial substance), HCl3 class (PSM17, solvent: toluene), HCl3 (PSM1, solvent: toluene), HCl1+HCl3 (PSM1, after next week of 40 DEG C/75%RH) and HCl3 (PSM1, after DVS).In XRPD figure in fig. 22, at least one or all following peaks with 2 θ number of degrees display HCl3: 8.2; 10.1; 10.9; 14.9; 16.0; 16.3; 16.8; 17.7; 18.7; 20.2; 22.9; 24.0; 25.6; 26.7; With 28.5.In certain embodiments, the feature of crystal form D is that XRPD figure comprises one or more following peak 2 θ: 8.2; 10.1; 14.9; With 25.6.In XRPD figure in fig. 22, at least one or all following peaks with 2 θ number of degrees display HCl3+HCl1: 6.5; 7.4; 12.5; 13.6; 14.1; 16.7; 17.4; 18.0; 19.3; 20.4; 21.8; 24.0; 25.1; 26.3; With 28.0.In certain embodiments, the feature of HCl3+HCl1 is that XRPD figure comprises one or more following peak 2 θ: 12.5; 19.3; With 26.3.In certain embodiments, the XRPD figure of crystal form D shows two peaks, three peaks, four peaks or five peaks.

With reference to Figure 23, measure hydrochloric acid by differential scanning calorimetry (DSC) and moor the fusing point that replaces the crystal form D (PSM1) of Buddhist nun.Use dry N ₂gas purification, under the rate of heat addition of 10 DEG C per minute, in the temperature range of 25 DEG C to 300 DEG C, analyzes sample in pin hole crucible.Strong endothermic event occurs in T _{peak value}=199.5 DEG C, T _{peak value}=204.1 DEG C and T _{peak value}at=257.6 DEG C.

With reference to Figure 24, provide TGA and the SDTGA Thermogram of crystal form D (PSM1).Mass loss 7.7% (toluene, API: solvent ratio is 1: 0.51) is observed in 120 DEG C-220 DEG C, temperature interval.

With reference to Figure 25, display 1750-500cm ^-1the FT-IR spectrum in region.These Data support hydrochloric acid moor the structure that crystal form D for Buddhist nun has proposition.In addition, this spectrum display crystal form D has unique property relative to crystal form A.

Carry out the experiment of the purity measuring crystal form D (PSM1).With reference to Figure 26, it is 97.3664% (area percentage) that mensuration hydrochloric acid moors that purity for the crystal form D of Buddhist nun.

the feature of crystal form E (mixture of HCl4+HCl1):

HCl4 is only to be obtained (general introduction see in Fig. 2) by the grinding experiment carried out with phenyl-hexafluoride with the form of mixtures of crystal form A.

Discovery hydrochloric acid is moored after that crystal form E for Buddhist nun stores at ambient conditions does not have physical stability.After storage 8 months, measure mixture HCl1+HCl4 again by XRPD, and it changes into crystal form A.

the feature of crystal form F (HCl5 class):

Form H Cl5 (general introduction see in Fig. 2) is obtained to diffusion experiment on solid by the steam carried out in butyl acetate described herein.HCl5 class is characterized by DSC, circulation-DSC, TGMS, FTIR, HPLC and DVS.Probe into the physical stability under short term stored condition (namely in next week of 40C and 75%RH).HCl5 class sample store 8 months at ambient conditions after there is physical stability, as by XRPD assess.In humidity chamber (40 DEG C/75%RH) after 1 week, material remains HCl5 class, but XRPD figure is slightly different.

DVS experiment display HCl5 class has very hygroscopic, and wherein water quality absorbs 37%.Its crystallinity of material forfeiture, as passed through indicated by XRPD after DVS experiment.

Use the condition identical with the condition of the Initial experiments in order to identify the polymorph previously found, under 120mg scale, success expands crystal form F in proportion.Carry out two and expand experiment in proportion, and corresponding XRPD figure instruction form and the same structure of HCl5.These are appointed as HCl5 class or crystal form F with version together with HCl5 and HCl5b.

The XRPD that Figure 27 shows the XRPD superposition of following thing schemes (from bottom to top): HCl1 (crystal form A initial substance); HCl5 and HCl5b (VDS28 is moistening and dry, solvent: butyl acetate); HCl5 class (VDS1, solvent: butyl acetate), low crystallization (VDS1, after DVS); HCl5 class (VDS2, solvent: butyl acetate); With HCl5 class (VDS2,40 °, after next week of 75%RH).In XRPD figure in figure 27, at least one or all following peaks with 2 θ number of degrees display HCl5: 6.8; 9.8; 12.4; 16.2; 17.9; 19.0; 24.0; With 25.1.In certain embodiments, the feature of HCl5 is that XRPD figure comprises one or more following peak 2 θ: 9.8; 12.4; With 25.1.In XRPD figure in figure 27, at least one or all following peaks (top pattern) with 2 θ number of degrees display HCl5 classes: 7.9; 8.7; 9.7; 11.4; 15.6; 16.5; With 25.8.In certain embodiments, the feature of HCl5 class is that XRPD figure comprises one or more following peak 2 θ: 15.6; 16.5; 25.8.In certain embodiments, the XRPD figure of crystal form F shows two peaks, three peaks, four peaks or five peaks.

With reference to Figure 28, measure hydrochloric acid by differential scanning calorimetry (DSC) and moor the fusing point that replaces the crystal form F (PSM1) of Buddhist nun.Use dry N ₂gas purification, under the rate of heat addition of 10 DEG C per minute, in the temperature range of 25 DEG C to 300 DEG C, analyzes the sample from two different experiments in pin hole crucible.Sample (VDS1, top curve) from an experiment confirms that strong endothermic event occurs in T _{peak value}=120.7 DEG C, T _{peak value}=184.3 DEG C and T _{peak value}=209.4 DEG C of places.Sample (VDS2, bottom curve) from another experiment confirms that strong endothermic event occurs in T _{peak value}=122.1 DEG C, T _{peak value}=209.7 DEG C and T _{peak value}=252.1 DEG C of places.

After circulation DSC experiment is presented at desolvation, HCl5 class changes into the form being appointed as " HCl5 desolventizing compound ", its melting at about 210 DEG C.

With reference to Figure 29, provide TGA/SDTA Thermogram (VDS1, top) and TGMS (bottom) Thermogram of crystal form F.Mass loss 17.1% (butyl acetate, API: solvent ratio 1: 1.01) is observed in 25 DEG C-160 DEG C, temperature interval.It is API that TG-MS analyzes display HCl5 class: butyl acetate ratio is the butyl acetate solvent compound of 1: 1, and its desolventizing at about 120 DEG C.Figure 30 is provided for corresponding TGA/SDTA (top) and TGMS (bottom) Thermogram of the crystal form F of VDS2.Mass loss 16.6% (butyl acetate, API: solvent ratio 1: 0.98) is observed in 25 DEG C-160 DEG C, temperature interval.

With reference to Figure 31 and 32, display 1750-500cm ^-1the FT-IR spectrum in region.These Data support hydrochloric acid moor the structure that crystal form F for Buddhist nun has proposition.In addition, these spectrum display crystal form F has unique property relative to crystal form A.

Carry out the experiment of the purity measuring crystal form F (VDS2).With reference to Figure 33, it is 98.2833% (area percentage) that mensuration hydrochloric acid moors that purity for the crystal form D of Buddhist nun.

the feature of crystal form G (HCl5b):

Under perfect vacuum after dry 3 days, moor by the acquisition hydrochloric acid that is converted of HCl5 the crystal form G that replaces Buddhist nun.Find that HCl5b form has physical stability after storing 8 months at ambient conditions.

The characterization data of crystal form G is provided when crystal form F herein.

the feature of form H (HCl6 class):

HCl6 is obtained by two experiments; Described experiment namely respectively at the steam carried out in MeOH/ water and MeOH solvent system in solution and steam to the experiment (general introduction see in Fig. 2) on solid.Different time points is slightly different to material sampling display corresponding XRPD figure, and under not bound by theory, instruction HCl6 is that a class may isostructural form.Use the condition identical with the condition that the MeOH steam of original screening experiment is tested on solid, the success of HCl6 class is extended to 120mg in proportion.

HCl6 class is characterized by DSC, circulation DSC, TGMS, FTIR, HPLC and DVS.Probe into the physical stability under short term stored condition (namely 40 DEG C and next week of 75%RH).Form H sample store 8 months at ambient conditions after there is physical stability, as by XRPD assess.In humidity chamber (40 DEG C/75%RH) after 1 week, material remains HCl6 class, but XRPD is slightly different.

Figure 34 shows XRPD figure (from bottom to top) of the XRPD superposition of following thing: crystal form A (hydrochloric acid moors that for Buddhist nun's initial substance), HCl6 class (VDS6, solvent: methanol), HCl6 class (VDS3, solvent: methanol), HCl6 (VDS3, after DVS), HCl6 class (VDS3, after climatic chamber), HCl6 class (VDS4, solvent: methanol) and HCl6 class (VDS4, after DVS).In the XRPD figure shown in Figure 34, at least one or all following peaks (abutting against more than crystal form A pattern) with 2 θ number of degrees display HCl6: 5.9; 8.1; 9.5; 10.7; 13.4; 16.0; 17.0; 22.0; 22.8; 24.7; With 28.3.In certain embodiments, the feature of HCl6 is that XRPD figure comprises one or more following peak 2 θ: 8.1; 10.7; 13.4; 24.7; With 28.3.In the XRPD figure shown in Figure 34, at least one or all following peaks (top pattern) with 2 θ number of degrees display HCl6 classes: 8.0; 10.2; 10.9; 11.8; 14.1; 15.4; 16.3; 19.9; 22.3; 23.7; 25.0; With 28.2.In certain embodiments, the feature of HCl6 class is that XRPD figure comprises one or more following peak 2 θ: 10.2; 15.4; 23.7; 25.0.In certain embodiments, the XRPD figure of crystal form F shows two peaks, three peaks, four peaks or five peaks.Although analyze all to be presented at after DVS operates to the XRPD of two samples and observe similar pattern, but analyze display methanol molecules to the TGMS of VDS4 to be no longer present in sample, but they are replaced (thus supposition forms half hydrated form belonging to HCl6 class) by hydrone.

With reference to Figure 35, measure hydrochloric acid by differential scanning calorimetry (DSC) and moor the fusing point that replaces the form H of Buddhist nun.Use dry N ₂gas purification, under the rate of heat addition of 10 DEG C per minute, in the temperature range of 25 DEG C to 300 DEG C, analyzes the sample from two different experiments in pin hole crucible.Sample (VDS3, top curve) from an experiment confirms at T _{peak value}there is strong endothermic event in=219.4 DEG C of places.Sample (VDS4, bottom curve) from another experiment confirms that strong endothermic event occurs in T _{peak value}=219.4 DEG C and T _{peak value}=256.8 DEG C of places.

With reference to Figure 36, provide TGA/SDTA Thermogram (VDS3, top) and TGMS (VDS3, the bottom) Thermogram of form H.Mass loss 5.4% (methanol is observed in 30 DEG C-150 DEG C, temperature interval, API: solvent ratio 1: 1.01), and in 190 DEG C-220 DEG C, temperature interval, observe mass loss 0.3% (methanol, API: solvent ratio 1: 0.05).Corresponding TGA/SDTA Thermogram (top) and TGMS (bottom) Thermogram of the form H of VDS4 is used in the display of Figure 37 place.Mass loss 3.3% (methanol is observed in 30 DEG C-150 DEG C, temperature interval, API: solvent ratio 1: 0.6), and in 190 DEG C-220 DEG C, temperature interval, observe mass loss 0.7% (methanol, API: solvent ratio 1: 0.12).

With reference to Figure 38 and 39, display 1750-500cm ^-1the FT-IR spectrum in region.These Data support hydrochloric acid moor the structure that form H for Buddhist nun has proposition.In addition, these spectrum display form H has unique property relative to crystal form A.

Carry out the experiment of the purity measuring form H (VDS4).With reference to Figure 40, it is 97.9794% (area percentage) that mensuration hydrochloric acid moors that purity for the form H of Buddhist nun.

the feature of crystalline form I (HCl6 desolventizing compound):

After the circulation DSC carried out with the empirical correlation of form H tests and is presented at desolvation, HCl6 class changes into the form being appointed as " HCl6 desolventizing compound ", its melting at about 220 DEG C.

the feature of crystal form J (HCl7):

Crystal form J is the pentahydrate that hydrochloric acid moors that replaces Buddhist nun, and is find when monocrystal analysis.Crystal form J is the most stable Hydrated structure of qualification, as shown in the competitive serosity of Yu Shuizhong between trihydrate and pentahydrate.

With obtaining in solvent mixture methanol/water (20: 80) and the diffusion of vapor experiment carried out as the n-butyl acetate of anti-solvent, there is the monocrystal of applicable size.Be about a kind of parallelepiped monocrystal of 0.45 × 0.25 × 0.12mm from crystallization bottle collection size, and lay on the glass fibers.Crystallography data (collecting until θ=27.5 °) is listed in table 4.

the crystal data of table 4: crystal form J and structure refinement

Identification code	Crystal form J (pentahydrate)
		D _c[g/cm ³]	1.352
μ[mm ^-1]	0.186
		F(000)	1384
Crystalline size [mm]	0.45×0.25×0.12
		For the θ scope [°] of data collection	2.8→27.5
The reflection number collected	24343
		Independently reflect number	7410[R _int＝0.0450]
The integrity degree [%] of θ=27.5 °	99.6
		Minimum and maximum transmission	0.9781 and 0.9211
Data/restriction/parameter	7410/0/542
		Based on F ²The goodness of fit	1.030
Final R index [l > 2 σ (l)]	R1＝0.0630，wR2＝0.1502
		R index (all data)	R1＝0.1064，wR2＝0.1758

Asymmetric cell comprises cation, cl anion and five hydrones (pentahydrate).Hydrone is connected with anion, cation and adjacent hydrone by hydrogen bond (H key).

The important results of the H key arrangement existed is the following fact: in this crystal, two kinds of electrically charged atoms (namely from protonated nitrogen and the cl anion of API) are by some hydrone bridge joint/separations.

Figure 43 shows hydrochloric acid and moors characteristic X-ray powder diffraction (XRPD) figure that replaces the crystal form J of Buddhist nun.The XRPD figure of the crystal form J shown in Figure 43 shows at least one or more with the 2 θ number of degrees to be had relative intensity 20% or is greater than the peak of 20%: 6.1; 7.0; 13.3; 16.4; 20.7; 22.2; 23.9; 25.5; With 29.1.In certain embodiments, the feature of crystal form J is that XRPD figure comprises one or more following peak 2 θ: 7.0; 22.2; With 25.5.In certain embodiments, the XRPD figure of crystal form J shows two peaks, three peaks, four peaks or five peaks.

the feature of crystal form K (HCl8):

Crystal form K is found when monocrystal analysis.Make monocrystal growth in the slow evaporation experiment carried out with TFE/H2O mixture (50: 50).Analyze a block sample monocrystal of size about 0.40 × 0.30 × 0.25mm.Although described crystal is comparatively large, its diffraction is very bad, and this instruction is at the partial order of configuration aspects.Therefore, only record until the measurement of θ=25 °.Crystallographic parameters is listed in table 5.

the crystal data of table 5: crystal form K and structure refinement

Identification code	Crystal form K (trifluoroethanol solvate hydrates)
		Crystalline size [mm ³]	0.40×0.30×0.25
For the θ scope [°] of data collection	2.1→25
		The reflection number collected	8812
Independently reflect number	5866[R _int＝0.0247]
		The integrity degree [%] of θ=25 °	99.0
Minimum and maximum transmission	0.9548 and 0.9290
		Data/restriction/parameter	5866/0/440
Based on F ²The goodness of fit	1.035
		Final R index [l > 2 σ (l)]	R1＝0.0762，wR2＝0.2160
R index (all data)	R1＝0.0931.wR2＝0.2366

The structure of mixing TFE solvation/hydrated form comprises cation, cl anion and two neutral entities: trifluoroethanol and hydrone.In this structure, although hydrone relates to H key, they do not separate electrically charged atom (contrary with three water forms with five water forms).TFE and hydrone only serve as the donor in hydrogen bond.Specifically for hydrone, only a hydrogen atom serves as donor, and this can cause the unordered and hydrone of hydrone not to be the stoichiometric fact compared to the ratio of API molecule.

Figure 44 shows hydrochloric acid and moors characteristic X-ray powder diffraction (XRPD) figure that replaces the crystal form K of Buddhist nun.The XRPD figure of the crystal form K shown in Figure 44 shows at least one or more with the 2 θ number of degrees to be had relative intensity 20% or is greater than the peak of 20%: 6.1; 7.4; 13.5; 17.4; 18.5; 20.7; 23.9; With 28.3.In certain embodiments, the feature of crystal form K is that XRPD figure comprises one or more following peak 2 θ: 7.4 and 23.9.In certain embodiments, the XRPD figure of crystal form K shows two peaks, three peaks, four peaks or five peaks.

hydrochloric acid moors the feature that replaces the amorphous form of Buddhist nun:

Figure 45 shows hydrochloric acid and moors that and moor that XRPD for Buddhist nun's (top pattern) for crystal form A (bottom pattern) of Buddhist nun and amorphous hydrochloric acid and scheme (solvent: 2,2,2 trifluoroethanols).Being easy to aobvious and easy to know is that crystal form A has one group of different peak under specific 2 θ angles, and amorphous hydrochloric acid is moored that and do not had for Buddhist nun and anyly determine peak.

In addition, amorphous hydrochloric acid is moored that and is moored that for Buddhist nun compared to amorphous hydrochloric acid and have unique melt temperature for crystal form A of Buddhist nun.Figure 46 shows amorphous hydrochloric acid and moors characteristic differential scanning calorimetry (DSC) Thermogram that replaces Buddhist nun.Observe peak value the strong endothermic event of 259.4 DEG C, described peak value corresponds to the fusing point of amorphous form.This fusing point is different from moors that fusing point replacing crystal form A of Buddhist nun (its display fusing point is 264.1 DEG C) to observe with hydrochloric acid.

Amorphous hydrochloric acid is moored that and is moored that uniqueness for the crystal form A of Buddhist nun for Buddhist nun and hydrochloric acid and different physical properties seems not owing to the purity of respective substance.When amorphous hydrochloric acid moors that for Buddhist nun, measure material by HPLC to have purity 99.7877% (area percentage) (see Figure 47), and measuring hydrochloric acid, to moor that purity of crystal form A for Buddhist nun be 99.8% (area percentage).

Embodiment 1

Find polymorphic forms

In order to find that hydrochloric acid is moored that initial trial for the polymorphic forms of Buddhist nun and is divided into two periods.1 phase comprised initial substance sign, feasibility test and solubility studies and thinks that 2 phases solvents are selected to provide data.2 phases be included in milliliter (ml) scale under 192 polymorph screening experiment of carrying out.These initially attempt causing discovery 8 kinds of polymorphic forms, i.e. crystal form A, crystal form B, crystal form C, crystal form D, crystal form E, crystal form F, crystal form G and form H.

1 phase: initial substance characterizes

About 24 grams of compound hydrochloric acid in faint yellow solid shape are provided to moor that for Buddhist nun.This initial substance is characterized by XRPD, digital image, DSC, TGMS and HPLC.Initial substance 3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl } benzamide monohydrochloride provides with crystalline material (being appointed as HCl1) form, and be 99.8% by the chemical purity that HPLC assesses it.Mass loss 0.7% (residual ethanol) in 25 DEG C-240 DEG C, temperature interval before TGA and TGMS analyzes and be presented at thermal decomposition process.Dsc analysis display T _{peak value}the endothermic event of=264.8 DEG C may with compound 3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl the melting of benzamide monohydrochloride and/or point decorrelation.

1 phase: solubility studies

Adopt one group of 20 kinds of solvent to moor that to hydrochloric acid and carry out quantitative dissolubility test for Buddhist nun's initial substance.At the little prepared slarry at present of equilibration time 24, after this Filter slurry.Dissolubility is measured by saturated solution by HPLC.Residual solid is characterized by XRPD.Result is summarized in table 6.

table 6:3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base]-4-methyl-N-{4-[4-methyl piperazine piperazine-1-base) methyl]-3-(trifluoromethyl) phenyl } solubility studies of benzamide monohydrochloride

All tests are all at room temperature under agitation carried out.

¹based on the solid form that XRPD analysis and evaluation is obtained by serosity.

²lower than scope, lower than detectability, concentration is lower than 0.22mg/ml

³overrun, substance dissolves, concentration is higher than 200mg/ml.

4 amorphous

In the experiment shown in 19 tables 6, the material of the post analysis of the dissolubility assessment carried out in 19 kinds of different solvents seems to have same form with the initial substance being appointed as form H Cl1.In the experiment QSA13 carried out in 2,2,2-trifluoroethanol, material dissolves completely under selected concentration, and the sample obtained after evaporating solvent produces amorphous substance.Solid from two kinds of serosity (QSA12 and QSA21) in water produce two kinds multi-form, be form H Cl2 and form H Cl2b respectively.After storing a couple of days at ambient conditions, form H Cl2 changes into form H Cl2b, and therefore it can not be characterized further.After characterizing further, determine that form H Cl2b is hydrated form (API/ water ratio 1: 1.4).

1 phase: feasibility study

Carry out feasibility test to attempt to obtain the amorphous initial substance in some crystallization techniques of the 2 phase parts that can be used for studying.Adopt two kinds of technology, i.e. grinding and lyophilization.Below present result.

Grinding.Under 30Hz frequency, twice grinding experiment is carried out by two various durations.After grinding 60 minutes, crystallization initial substance changes into amorphous.After 120 minutes, amorphous is held in gains quality guarantee, and its chemical purity is 99.6%.

Lyophilization.With 3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl } benzamide monohydrochloride carry out eight lyophilizations experiment.These General description of experiments are in table 7.

table 7:3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{4-[(4-methyl piperazine piperazine-1-base) methyl]-3-(trifluoromethyl) phenyl } lyophilization of benzamide monohydrochloride is feasible journal of Sex Research

1 based on TGMS result. ²by the chemical purity that HPLC measures.

Compound hydrochloric acid moors that is too low so that can not with good condition application lyophilization program for the dissolubility of Buddhist nun in oxolane, 2-methyltetrahydrofuran and dichloromethane.Under the solvent of such as methanol, 2,2,2-trifluoroethanols (TFE) and TFE/ aqueous mixtures, obtain amorphous substance.In the sample obtained from pure TFE or the solvent mixture higher with TFE content, in dried powder, the residual solvent (according to TGMS result) of 11% detected.The sample obtained from methanol and TFE/ water (50: 50) respectively containing only 0.9% and 1.5% less residual solvent.After extra dry 24 hours, in the amorphous substance that TFE/ water (50: 50) produces, the amount of residual solvent can be reduced to lower than 1%.For two amorphous samples obtained from methanol and TFE/ water (50: 50), the chemical purity assessed by HPLC is 99.8%.Because observe creep in the lyophilization experiment carried out with methanol, so the program of choice for use TFE/ water (50: 50) moors that for Buddhist nun for generation of the cooling-evaporative crystallization and steam being ready to use in for 2 phases to the amorphous hydrochloric acid in diffusion experiment on solid.

2 phases: polymorph finds

Use 192 kinds of different conditions under milliliter (ml) scale, carry out hydrochloric acid and moor the polymorph screening experiment that replaces Buddhist nun, wherein apply 6 kinds of different crystallization procedure: (1) cooling-evaporation; (2) anti-solvent is added; (3) grind; (4) pulp; (5) steam spreads in solution; (6) steam spreads on solid.After completing screening experiment, collection of material, and analyzed by XRPD and digital image.

Cooling-evaporative crystallization is tested.Adopt 36 kinds of different solvents and solvent mixture and a kind of concentration, under milliliter scale 36 cooling-evaporation experiments carry out table 8 in 1.8ml bottle shown in.In each bottle, 25mg amorphous hydrochloric acid of weighing moors that for Buddhist nun.Then add screening solvent and be about 60mg/ml to reach concentration.The airtight bottle also containing magnetic stirring bar, and be placed in AvantiumCrystal16 to stand Temperature Distribution (as described in the following table 9).Cooling mixture to 5 DEG C, and keep 48 hours at that temperature, subsequently bottle is placed under vacuo.Evaporating solvent a couple of days under 200mbar or 10mbar, and analyzed by XRPD and digital image.

table 8: the experiment condition for 36ml experiment using cooling-method of evaporating

table 9: for the Temperature Distribution of 36 cooling-evaporation experiments

Experiment	The rate of heat addition	T _Initially	Keep	Cooldown rate	T _Finally	Keep
							PSM1-36	10	60	60	1	5	48

Add the collision crystallization experiment of anti-solvent.For collision crystallization experiment, use a kind of solvent anti-solvent different from 24 kinds (see table 9), apply 36 kinds of different crystallization conditions.Anti-solvent is added experiment and is carried out forward.Prepare liquid storage, it is the concentration obtained in the saturated condition at ambient temperature after 24 hours at the forward horizontal stand be filtered in 8ml bottle for concentration of Buddhist nun that hydrochloric acid moors that.Use solvent and anti-solvent ratio 1: 0.25, in each these bottles, add different anti-solvent.Because do not precipitate, so this ratio is increased to 1: 4, the waiting time between wherein adding for each time is 60 minutes.When still there is not precipitation, at room temperature complete evaporating solvent under vacuo.After evaporation, experiment causes not having productive rate.

table 9: collision crystallization experiment

Grinding experiment.Drip grinding technique use and be added into material 3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl } a small amount of solvent in benzamide monohydrochloride, grinds in stainless-steel grinding tank with 2 stainless-steel grinding balls.In this way, the impact of 24 kinds of different solvents (see table 10) is probed into.Usually, 30mg initial substance is weighed in grinding container, and add 10 μ l solvents in container.Grinding experiment was carried out 120 minutes periods under 30Hz.Each moistening material is analyzed subsequently by XRPD and digital image.

table 10: for the experiment condition of grinding experiment

Experiment	Solvent	Weight (mg)	Volume (μ l)
				GRP1	Phenyl-hexafluoride	30.6	10
GRP2	Cyclohexane extraction	31.4	10
				GRP3	Acetonitrile	28.8	10
GRP4	Ethylene glycol dimethyl ether	28.6	10
				GRP5	Diethoxymethane	29.9	10

Experiment	Solvent	Weight (mg)	Volume (μ l)
				GRP6	Normal heptane	31.0	10
GRP7	Pure isooctane	31.0	10
				GRP8	Water	30.0	10
GRP9	Nitrocarbol.	30.0	10
				GRP10	Isosorbide-5-Nitrae-diox	29.8	10
GRP11	α, α, α-benzotrifluoride	30.5	10
				GRP12	Toluene	30.4	10
GRP13	2-nitropropane	30.3	10
				GRP14	1-nitropropane	30.4	10
GRP15	Xylol	30.6	10
				GRP16	N octyl fluoride	30.6	10
GRP17	Isoamyl acetate	30.3	10
				GRP18	O-Dimethylbenzene	29.0	10
GRP19	N-nonane	29.6	10
				GRP20	Ketohexamethylene	29.8	10
GRP21	Diethylene glycol-dimethyl ether	29.7	10
				GRP22	Sec-butylbenzene	29.1	10
GRP23	Decane	28.9	10
				GRP24	(R)-(+)-limonene	28.6	10

Slurry experiment.Moor that with compound hydrochloric acid to continue within 2 weeks, to carry out total 48 slurry experiment at 10 DEG C and 30 DEG C for Buddhist nun and 24 kinds of solvents.Experiment condition summarized by table 11.Test by stirring the suspension of material in solvent at controlled.At the end of slurry time, bottle is centrifugal, and separating solids and mother solution.At room temperature further drying solid under perfect vacuum, and analyzed by XRPD and digital image.

table 11: for the experiment condition of slurry experiment

Steam spreads in solution.For diffusion of vapor experiment, at room temperature make hydrochloric acid moor that saturated solution for Buddhist nun and be exposed to solvent vapo(u)r two weeks.The saturated solution of certain volume is transferred in unlimited 8ml bottle, and is placed on and has in the airtight 40ml bottle of 2ml anti-solvent (see table 12).After the two weeks, the solid of sample for reference is formed.Drying sample under vacuum (200mbar or 10mbar), and cause not there is productive rate.Based on result, carry out additional experiments with 12 kinds of different crystallization conditions as described in table, namely test IDVDL25-VDL36.

table 12: the experiment condition spread in solution for steam

Steam spreads on solid.For diffusion of vapor experiment, at room temperature make amorphous hydrochloric acid moor that and be exposed to solvent vapo(u)r two weeks for Buddhist nun.The 8ml bottle with amorphous API is opened wide, and is placed in the airtight 40ml bottle with 2ml anti-solvent (see table 13).After the two weeks, solid is analyzed by XRPD and digital image.If solid is by steam liquefied, then drying sample under vacuum (200mbar or 10mbar), analyzes them by XRPD and digital image subsequently.

table 13: the experiment condition spread on solid for steam

In crystallization experiment between these initial trial periods, the XRPD of drying (and if the applicable moistening) sample obtained is analyzed and discloses except amorphous substance and initial substance crystal form A, also there are 7 kinds of other polymorphic forms.Described 7 kinds of forms are appointed as HCl2, HCl2b, HCl3 class, HCl5, HCL5b, HCl6 class and mixture HCl1+HCl4.

Be presented in Fig. 2 at the multi-form occurrence rate of these 2 interim acquisitions initially attempted.Obtain XRPD figure and the digital picture of each form that representative obtains in the experiment of these 2 phases.The sign of the form of the 1 interim acquisition initially attempted at these is summarized in table 14.

table 14: hydrochloric acid moors the sign that replaces some polymorphic forms of Buddhist nun

^aoccurrence rate: total occurrence rate is included in 2 interim 216 experiments carried out, for described experiment, humid analysis 39 samples or evaporation analyze mother solution in addition, thus provide the material of total 254 sign.For example, " (3,1.2%) " occurs 3 times in measuring at 254 times corresponding to described form, thus provides the percentage ratio of 1.2%.62 times (9%) in measuring for 254 times, the products collection efficiency of some products or scattering strength are too low so that can not identify solid form, or material is moistening.

^bcrystallisation mode: cool-evaporation (PSM), add the collision crystallization (AS) of anti-solvent, grind (GRP), pulp (SLP), steam spreads (VDS) on solid and steam spreads (VDL) in solution.Lyophilization (FD) is for generation of amorphous substance (see the experiment of 1 phase).QSA (quantitative solubility experiment), see the experiment of 1 phase.

^caccording to the Solvation State of TGMS outcome evaluation.

^daccording to the heat absorption of DSC outcome evaluation.

^eaccording to the chemical purity of HPLC outcome evaluation.

^fdo not measure in this experiment.

^gby the structure that monocrystal analysis is determined.

The polymorphic forms specifying in and identify and be shown in Fig. 2 in these 1 phases and the experiment of 2 phases is mainly analyzed according to XRPD.In the process that this is analyzed, observe some patterns, in the general fingerprint of XRPD figure, there is similarity, but show some little differences, as peak-shift or less extra peak.Being trooped by the pattern of these types is a class pattern (such as HCl3 class).Based on XRPD, infer that the similarity between the XRPD figure in a certain classification is illustrated by the following fact: these solid forms are isomorphism hydrate/solvate (similar crystal accumulations, but slightly different by being incorporated to the unit cell parameters that different solvents and water causes in crystal structure).

All kinds of isomorphism solvate is specified by numeral (HCl3 class) or numeral-monogram (such as HCl2 and HCl2b).The minority subclass (such as HCl2 and HCl2b) that this classification is observed in the isomorphism solvates/hydrates classification instruction of specifying in an experiment is combined by alphabet-numeric playing.When identifying more than three subclass in classification, all XRPD figure corresponding to a class isomorphism solvates/hydrates divide into groups (such as HCl3 class) again according to a numeral.

The similarity degree of their the XRPD figure of isomorphism solvate display in a certain classification or between the classification of specifying by same numeral is higher than the similarity degree when the isomorphism solvate classification of specifying with different digital.For these inhomogeneous isomorphism hydrate/solvates, larger XRPD figure difference reflection crystal structure is piled up significantly different.

In some XRPD figure, the form compared to qualification observes one or two extra peak.Because form known clearly can not be appointed as in these peaks, so they are indicated as " additional peak ".

Embodiment 2

Further discovery polymorphic forms

Carry out follow-up trial to analyze 3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl } monocrystal of benzamide monohydrochloride.This type of attempts the pseudopolymorph causing discovery 5 kinds different, and two wherein in these other polymorphic forms is previously undiscovered.These two kinds of newfound polymorphic forms are appointed as HCl7 (in this article also referred to as " crystal form J ") and HCl8 (in this article also referred to as " crystal form K ") in this article.In these are tested subsequently, three kinds of different crystallization techniques are for making the single crystal growth with applicable size to analyze: (1) slow evaporation recrystallisation solvent; (2) anti-solvent is made to 3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl } spread in the solution of benzamide monohydrochloride; And (3) temperature crystallization control.In a word, in these are tested subsequently, carry out 54 crystallization experiments replaces the single crystal growth of the hydrated form of Buddhist nun to determine structure to attempt making hydrochloric acid moor that.

About temperature crystallization control, prepare 24 experiments with the mixture (see table 15) of alcohol and water.For each experiment, 10mg hydrochloric acid is used to moor that for Buddhist nun.By the mixture Fast Heating of API and solvent until 80 DEG C, and slowly cool to room temperature (0.1 DEG C/min).

table 15: the experiment condition of temperature crystallization control experiment

Spread in solution about steam, carry out 25 experiments.For each experiment, 10mg hydrochloric acid is moored that and be dissolved in the mixture of 1mlTFE/ water (10: 90) or MeOH/ water (30: 70) for Buddhist nun.Each solution is placed in 6ml bottle, described bottle is inserted in the 20ml bottle containing 3ml anti-solvent.Bottle is kept at room temperature 2-4 week.Details is reported in table 16.

table 16: the experiment condition of diffusion of vapor experiment

About slow evaporation solvent, 10mg hydrochloric acid is moored that and be placed in 8ml bottle for Buddhist nun, and add 2ml solvent (mixture of solvent).Wherein in solid those situations undissolved, heating bottle to 90 DEG C.Subsequently, mixture is made to slowly cool to room temperature (see table 17).For the experiment 53 of last in table 17, material dissolves not yet completely after keeping a few hours at 90 DEG C.

table 17: the experiment condition of slow evaporation experiment

Each polymorphic forms disclosed herein uses hydrochloric acid to moor that to be obtained by specific crystallization/solvent pattern as initial substance for Buddhist nun.Although previously described hydrochloric acid to moor the synthesis (such as WO2007/075869 and WO2011/053938) that replaces Buddhist nun, following hydrochloric acid has been moored that and has been provided in embodiment 6 place for Buddhist nun's synthesis.

Embodiment 3

Hydrochloric acid moors the stress test that replaces Buddhist nun's crystal form A

Crystal form A is a kind of crystal anhydrous solid that can reappear acquisition from the solvent of certain limit.Form H Cl-1 has intrinsic chemical stability, and this is directly relevant to the thermodynamic stability of HCl1 form.Form H Cl-1 is to heat, pressure and humidity modification and be exposed to some solvent vapo(u)rs and stablize, and has thermodynamic stability.Carry out numerous research to confirm that it is in preparation (tablet) state and the stability do not prepared under (crude drug) state.Result of this type of research is provided in the following table in 18:

table 18: the stress studies that replaces Buddhist nun's crystal form A is moored to hydrochloric acid

Form H Cl-1 is to heat, pressure and humidity modification and be exposed to some solvent vapo(u)rs and stablize, and is the maximum solid form of the thermodynamic stability that is separated up to now.

Carry out the physical stability of testing to test form H Cl1 as follows:

50: 50 physical mixtures of form H Cl1 and HCl1 and amorphous substance are made to be exposed to alcohol vapour two weeks (see diffusion of vapor experiment).50 and 100kN/cm is stood by making form H Cl1 ²the pressure of (or 4 and 8 tons/square centimeter) prepares tablet in 10 seconds.At ambient conditions crystal form A is stored in capsule and reaches 17 months.These samples are analyzed by high-resolution XRPD.

The result obtained is summarized in table 19, and obtains XRPD measurement result and digital picture.They are presented in the stress condition of applying, and polymorphic crystalline form HCl1 remains unchanged, thus confirm its good physical stability.

the result of the follow up study of table 19. pair crystal form A

Embodiment 4

The stability of some polymorphic forms

Select the sample of 8 kinds of solid forms of hydrochlorate to study their physical stability.Two samples of each relevant polymorphic forms of the hydrochlorate selecting representative to obtain.Each sample is analyzed again by XRPD.Described form stores the physical stability after 8 months at ambient conditions.Result is summarized as follows:

Under the condition of probing into, HCl1, HCl2b, HCl3 class, HCl5b and HCl6 class have physical stability;

HCl2 changes into HCl2b (this conversion occurred after 1 day stored sample at ambient conditions);

HCl5 changes into HCl5b (this having occurred after dry 3 days under perfect vacuum transform);

At ambient conditions after 8 months, mixture HCl1+HCl4 changes into HCl1.

the physical stability of each hydrochloride form of table 20.

^ainitial substance (SM): the form H Cl1 obtained by lyophilization or amorphous substance (Am). ^bas after completing crystallization experiment by XRPD classify.

^ccrystallisation mode: cool-evaporation (PSM), add the collision crystallization (AS) of anti-solvent, grind (GRP), pulp (SLP), steam spreads (VDS) on solid and steam spreads (VDL) in solution.QSA (quantitative solubility experiment).

^daccording to the Solvation State of TGMS outcome evaluation.

^end=does not measure.

^frespectively at room temperature storing 1 day or under vacuo after dry 3 days, HCl2 and HCl5 changes into HCl2b and HCl5b.

Embodiment 5

Prepare crystal form A

Moor for forming hydrochloric acid with crystalline material form in the alcoholic solution of Buddhist nun's free alkali the crystal form A that replaces Buddhist nun to mooring that by adding the solution of HCl (1.0 equivalent) in ethanol.Make crude drug (hydrochloric acid moors that for Buddhist nun) crystallization in the final step of described crude drug building-up process by adding kind of a crystalline substance, this measure produces extremely consistent and distinctive granularity and the scope of crude drug.Last 10 thousands of grams of (multi-kilogram) scale batches moor that in the hydrochloric acid of HCl-1 form for the ethanol content in Buddhist nun in the scope of 0.8-1.2%.

The sign of ethanol or water is not found in HCl-1 form; Therefore crystal form A is dehydrate.In addition, the crystal accumulation of HCl-1 form is not containing the space that can hold ethanol or other organic molecule.In order to probe into ethanol content and during drying from hydrochloric acid moor that for Buddhist nun remove ethanol other research indicated hydrochloric acid moor that for Buddhist nun crystal form A in, ethanol seems to associate with plane of crystal.

The feature of form H Cl-1 is all under the level of about 1 % by weight, unanimously there is residual ethanol in the crude drug of all batches.Crystallography research and other research have been presented on plane of crystal exists (retaining) residual ethanol, and is not a part for crystallization unit cell, and HCl-1 is not ethanol solvate or passage solvate.Levels of ethanol in the end in ten number kilogramme-scale crude drug batch is in the scope of 0.8 to 1.2%.

iI. the polymorphic forms that replaces Buddhist nun's free alkali is moored

In synthesis chapters and sections of the present disclosure, (see flow process 1) shows and that preparation for Buddhist nun's free alkali initial substance (AP23534) of pool is discussed below.Following elaboration herein of the present disclosure be entitled as " to that feasibility study for Buddhist nun's free alkali compound of pool" chapters and sections in the preparation of amorphous free alkali is discussed.

Analyzed by XRPD, start from mooring that for Buddhist nun's free alkali initial substance, find to moor total 11 kinds of polymorphic forms that replaces Buddhist nun, comprise dehydrate and hydrate, solvate and isomorphism hydrate/solvate form thereof.11 kinds of Novel polymorphic Form are referred to herein as: crystal form A, crystal form B (or category-B form), crystal form C, crystal form D, crystal form E (or E class), crystal form F, crystal form G, form H (or H class form), crystalline form I, crystal form J and crystal form K.

Anhydrate crystal form A (fusing point ~ 200 DEG C) is the predominant crystalline found in screening.Crystal form B comprises 4 kinds of isomorphism solvates, i.e. 1: 1 diox solvate, 1: 1 perfluor solvate, 1: 0.42-methyl THF solvate and 1: 1 cyclohexanone solvent compound.Crystal form E comprises chloroform and dichloromethane isomorphism solvate.Crystal form D is solvation form (such as DMA).Crystal form F is single hydrated form.Form H comprises 2 kinds of isomorphism solvates, i.e. 1: 0.61-propanol solvate and 1: 0.932-methoxyethanol solvent compound.

The appointment of the form obtained in 3 phases and the experiment of 4 phases is mainly analyzed based on XRPD.Thus, can be observed some patterns, in the general fingerprint of XRPD figure, there is similarity, but show some little differences, as peak-shift and/or little extra peak.Being trooped by the pattern of these types is a class pattern (such as category-B).Based on XRPD, similarity between XRPD figure in a certain classification can indicate these solid forms to be isomorphism hydrate/solvate (similar crystal accumulations, but slightly different by being incorporated to the unit cell parameters that different solvents and water causes in crystal structure).All kinds of isomorphism solvate is specified by letter (category-B).

In some XRPD figure, the form compared to various qualification observes one or more extra peak.Because form known clearly can not be appointed as all the time in these peaks, so they are indicated as " additional peak " (such as " crystal form F additional peak ") when in place.

That screening of polymorph for Buddhist nun of pool is included in the method for crystallising of 6 types that milliliter scale is carried out.Described method comprises: the collision crystallization adding anti-solvent; Grinding; Slurry experiment; Steam spreads in solution; Cooling-evaporative crystallization; Spread on solid with steam.These are more than discussed and moor for the preparation of various hydrochloric acid the method that replaces Buddhist nun's polymorph.Below by discuss described method be applied to pool that for Buddhist nun's free base polymorph thing time any difference.

The crystal structure of crystal form A and 2 kinds of crystal form B solvates is determined by single-crystal X-ray data analysis.The solvent that these researchs show in the conformation and 2 kinds of crystal form B solvates adopted in crystal structure by crystal form A is included in.

In general, those these various crystal forms for Buddhist nun of pool disclosed herein are moored that for Buddhist nun compared to amorphous and are had the physical property (as high stability etc.) being conducive to business and preparing solid dosage forms.Crystallization is moored that and is moored that for Buddhist nun and amorphous and can be easy to for distinguishing pool disclosed herein for the difference between Buddhist nun that replaces physical-chemical data (such as DSC, XRPD, thermal analyses) of the identical type of indivedual crystal forms of Buddhist nun to observe.

Figure 48 and 49 provides for that tabulars general introduction provided for 10 kinds in 11 kinds of solid forms of Buddhist nun of pool, and described 10 kinds of forms comprise the crystal form A that is accredited as disclosed herein to the polymorph of J and pseudopolymorph.(crystal form K will discuss separately as follows in this article, and is not a part for this tabular general introduction).Figure 48 and 49 provides that source for Buddhist nun's polymorph of pool, occurrence rate and various feature jointly.

With reference to Figure 48, " LC " refers to that the low crystallization as the initial substance of other polymorph various moors that for Buddhist nun (such as crystal form C)." A " refers to that it can be used for preparing other form by above-mentioned various crystallisation mode as that crystal form A enriching crystal form most for Buddhist nun of pool.The footnote appeared in the table of Figure 48 is as follows:

(a) as after completing crystallization experiment by XRPD classify;

(b) crystallisation mode: cool-evaporation (PSM), add the collision crystallization (AS) of anti-solvent, grind (GRP), pulp (SLP), steam spreads (VDS) on solid and steam spreads (VDL) in solution.Lyophilization (FD) is for generation of low crystalline material (see the experiment of 3 phases).QSA: quantitatively solubility experiment (3 phase);

(c) occurrence rate: total occurrence rate is included in 4 interim 192 experiments carried out, for described experiment, humid analysis 61 samples or evaporation analyze mother solution in addition, thus provide the material of total 253 sign.For example, " (6,2.4%) " occurs 6 times in measuring at 253 times corresponding to described form, thus provides the percentage ratio of 2.4%.4 times (1.6%) during 253 times are measured, the products collection efficiency of some products or scattering strength are too low so that can not identify solid form, or material is moistening;

(d) PO: preferred orientation effect; And

(e) initial substance: the crystal form A obtained by lyophilization or low crystallization (LC) material.

With reference to mooring the preceding method that replaces Buddhist nun's polymorph for assessment of hydrochloric acid, 3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl is below discussed } polymorph of benzamide free base.

moor the feature that replaces Buddhist nun's crystal form A

Anhydrate crystal form A (crystal form identical with initial substance) is the predominant crystalline found in screening.Moor that chemical constitution for Buddhist nun's crystal form A clearly to be determined by single-crystal X-ray crystallography.That solid form for Buddhist nun of the pool observed is anhydrous crystal solid crystalline A.

Figure 50 represents the crystal form A obtained by single-crystal X-ray diffraction and moors that molecular structure for Buddhist nun's free alkali compound (dehydrate) and numbering plan.Based on this structural analysis, determine that crystal form A is anhydrous form.

The crystallography data (collecting until θ=26 °) of anhydrate crystal form A is listed in table 21.

table 21: moor that crystal data for Buddhist nun's crystal form A and structure refinement

Identification code	S10010A_AS37
		The integrity degree [%] of θ=26 °	99.6
Minimum and maximum transmission	0.9810 and 0.9598
		Data/restriction/parameter	5340/0/357
Based on F ²The goodness of fit	1.023
		Final R index [l > 2 σ (l)]	R1＝0.0583，wR2＝0.1371
R index (all data)	R1＝0.0932，wR2＝0.1612
		Extinction coefficient	0.044(5)

Figure 51 presents experiment XRPD figure and the comparing of calculating pattern (wherein the FWHM=0.1 °) based on the crystal structure determined crystal form A.The crystal structure of the tight similarity instruction crystal form A of two XRPD figure represents cake mass.

In the XRPD figure shown in Figure 51, at least one or all following peaks with 2 θ number of degrees display crystal form As: 6.2; 8.8; 9.9; 11.2; 12.3; 12.9; 13.5; 13.8; 14.2; 14.4; 16.0; 16.4; 17.2; 17.6; 18.0; 18.2; 19.3; 19.5; 19.8; 20.6; 21.5; 21.9; 22.2; 22.6; 23.1; 24.0; 24.4; 25.1; 25.6; 25.9; 26.8; 27.4; 27.8; 29.1; With 29.8.In certain embodiments, the feature of crystal form A is that XRPD figure comprises one or more following peak 2 θ: 6.2; 12.3; 13.8; 14.4; 16.0; 16.4; 17.2; 17.6; 18.2; 19.5; 19.8; 20.6; 21.5; 22.2; 24.0; 25.9; 26.8; 27.4; With 27.8.In the XRPD figure shown in Figure 51, at least one or all following peaks with 2 θ number of degrees display crystal form As: 12.3; 13.8; 14.4; 17.6; 19.8; 20.6; 21.5; 22.6; With 24.0.In certain embodiments, the feature of crystal form A is that XRPD figure comprises one or more following peak 2 θ: 12.3; 13.8; 17.6; 19.8; 20.6; 21.5; 22.6; With 24.0.In certain embodiments, the XRPD figure of crystal form A shows two peaks being selected from those peaks above, three peaks, four peaks or five peaks.In certain embodiments, moor that feature for the crystal form A of Buddhist nun's free alkali and be that the top XRPD that XRPD figure is substantially similar in Figure 51 schemes (acquisition).In certain embodiments, crystal form A comprises the characteristic peak such as the bottom (simulation) in Figure 51 or the XRPD as shown in top (acquisition) pattern that represent with the 2 θ number of degrees and schemes.

With reference to Figure 52, measure that fusing point for Buddhist nun of pool in anhydrate crystal form A by differential scanning calorimetry (DSC).Use dry N ₂gas purification, under the rate of heat addition of 10 DEG C per minute, in the temperature range of 30 DEG C to 350 DEG C, in pin hole crucible, analyze those two samples for Buddhist nun of pool, namely AP24534 lot number 1285.206A (with 1-PrOH process) and AP24524 lot number 1-PrOH is untreated.Observe peak value at the endothermic event of 199.6 DEG C, described peak value corresponds to that fusing point for Buddhist nun's crystal form A of pool.

moor the feature that replaces Buddhist nun's crystal form B (category-B) polymorph

Moor the feature that replaces Buddhist nun/Isosorbide-5-Nitrae-diox 1: 1 solvate crystalline B

Single-crystal X-ray diffraction analysis is used for the crystal structure determining 1: 11,4-diox solvate crystalline B.Figure 53 represents molecular structure and the numbering plan of 1: 11, the 4-diox solvate crystalline B obtained by single-crystal X-ray diffraction.

The crystallography data (collecting until θ=27.4 °) of 1: 11,4-diox solvate crystalline B is listed in table 22.

table 22: moor that crystal data for Buddhist nun/Isosorbide-5-Nitrae-diox 1: 1 solvate crystalline B and structure refinement

Identification code	S10010A_PSM32
		F(000)	652
Crystalline size [mm ³]	0.40×0.36×0.10
		For the θ scope [°] of data collection	3→27.4
The reflection number collected	11721
		Independently reflect number	7312[R _int＝0.0330]
The integrity degree [%] of θ=27.4 °	99.0％
		Minimum and maximum transmission	0.9906 and 0.9631
Data/restriction/parameter	7312/6/411
		Based on F ²The goodness of fit	1.032
Final R index [l > 2 σ (l)]	R1＝0.0945，wR2＝0.2337
		R index (all data)	R1＝0.1580，wR2＝0.2815
Extinction coefficient	0.023(5)

Figure 54 presents based on the calculating pattern to that crystal structure determined for Buddhist nun/Isosorbide-5-Nitrae-diox 1: 1 solvate crystalline B of pool.

In the XRPD figure shown in Figure 54, with 2 θ number of degrees display pool those at least one or all following peaks for Buddhist nun/Isosorbide-5-Nitrae-diox 1: 1 solvate crystalline B: 5.6; 7.2; 9.8; 10.8; 12.1; 12.5; 12.8; 14.5; 15.3; 15.8; 17.0; 17.3; 17.5; 18.5; 19.0; 19.5; 20.0; 20.3; 21.1; 21.6; 22.4; 22.8; 23.5; 24.1; 24.5; 25.3; 26.0; 26.4; 27.0; 27.5; 28.4; 30.8; With 32.0.In certain embodiments, moor that feature for Buddhist nun/Isosorbide-5-Nitrae-diox 1: 1 solvate crystalline B and be that XRPD figure comprises one or more following peak 2 θ: 5.6; 10.8; 12.1; 14.5; 15.3; 15.8; 17.0; 17.3; 18.5; 19.0; 20.0; 20.3; 21.6; 22.4; 24.5; With 26.0.In the XRPD figure shown in Figure 54, with 2 θ number of degrees display pool those at least one or all following peaks for Buddhist nun/Isosorbide-5-Nitrae-diox 1: 1 solvate crystalline B: 5.6; 12.1; 14.5; 15.3; 15.8; 17.3; 18.5; 19.0; 20.3; 21.6; With 26.0.In certain embodiments, moor that feature for Buddhist nun/Isosorbide-5-Nitrae-diox 1: 1 solvate crystalline B and be that XRPD figure comprises one or more following peak 2 θ: 5.6; 14.5; 15.3; 15.8; 19.0; 20.3; With 26.0.In certain embodiments, moor that XRPD figure for Buddhist nun/Isosorbide-5-Nitrae-diox 1: 1 solvate crystalline B and show two peaks being selected from above those peaks provided, three peaks, four peaks or five peaks.In certain embodiments, moor that feature for Buddhist nun/Isosorbide-5-Nitrae-diox 1: 1 solvate crystalline B and be that XRPD figure is substantially similar to the XRPD figure in Figure 54.In certain embodiments, mooring that for Buddhist nun/Isosorbide-5-Nitrae-diox 1: 1 solvate crystalline B is crystallization.

Moor the feature that replaces Buddhist nun/perfluor benzene 1: 1 solvate crystalline B

Single-crystal X-ray diffraction analysis is used for the crystal structure determining 1: 1 perfluor benzene solvent crystal form B.Figure 55 represents molecular structure and the numbering plan of 11: the 1 perfluor benzene solvent crystal form Bs obtained by single-crystal X-ray diffraction.Similarity between the unit cell of Isosorbide-5-Nitrae-diox solvate and fluorobenzene solvate and crystal accumulation confirms that crystal form B class material is isomorphism solvate.

The crystallography data (collecting until θ=27.6 °) of 1: 1 perfluor benzene solvent crystal form B is listed in table 23.

table 23: moor that crystal data for Buddhist nun/perfluor benzene 1: 1 solvation form and structure refinement.

Identification code	S10010A_VDL6
		For the θ scope [°] of data collection	3→27.6
The reflection number collected	10370
		Independently reflect number	7321[R _int＝0.0315]
The integrity degree [%] of θ=27.6 °	96.9
		Minimum and maximum transmission	0.9811 and 0.9583
Data/restriction/parameter	7321/0/381
		Based on F ²The goodness of fit	1.052
Final R index [l > 2 σ (l)]	R1＝0.0885，wR2＝0.2377
		R index (all data)	R1＝0.1181，wR2＝0.2691
Extinction coefficient	0.127(16)

Figure 56 shows experiment XRPD figure and the comparing of calculating pattern (wherein the FWHM=0.1 °) based on the crystal structure determined crystal form B 1: 1 perfluor solvate.The crystal structure of tight similarity instruction crystal form B 1: the 1 perfluor benzene of two XRPD figure represents cake mass.

In the XRPD figure shown in Figure 56, moor that at least one or all following peak for Buddhist nun/perfluor solvate with 2 θ number of degrees display crystal form Bs 1: 1: 7.0; 8.2; 9.8; 11.0; 11.5; 12.4; 12.8; 124.0; 14.4; 15.3; 16.0; 16.6; 17.2; 18.2; 19.0; 19.5; 20.0; 20.1; 21.1; 22.0; 22.5; 22.7; 23.5; 24.0; 24.5; 25.1; 26.0; 27.0; 27.8; 28.2; 31.8; With 35.4.In certain embodiments, crystal form B 1: 1 is moored that feature for Buddhist nun/perfluor solvate and is that XRPD figure comprises one or more following peak 2 θ: 5.6; 11.0; 12.4; 12.8; 14.4; 15.3; 16.0; 16.6; 17.2; 18.2; 19.0; 20.1; 22.0; 22.5; 22.7; 23.5; 24.5; 26.0; With 28.2.In the XRPD figure shown in Figure 56, moor that at least one or all following peak for Buddhist nun/perfluor solvate with 2 θ number of degrees display crystal form Bs 1: 1: 5.6; 12.4; 15.3; 16.0; 19.0; 20.1; 22.0; 22.5; 22.7; With 26.0.In certain embodiments, crystal form B 1: 1 is moored that feature for Buddhist nun/perfluor solvate and is that XRPD figure comprises one or more following peak 2 θ: 5.6; 12.4; 15.3; 22.0; With 26.0.In certain embodiments, that XRPD figure for Buddhist nun/perfluor solvate of crystal form B 1: 1 pool shows two peaks, three peaks, four peaks or five peaks.In certain embodiments, crystal form B 1: 1 is moored that feature for Buddhist nun/perfluor solvate and is that the top XRPD that XRPD figure is substantially similar in Figure 56 schemes.In certain embodiments, crystal form B 1: 1 is moored that feature for Buddhist nun/perfluor solvate and is that the bottom XRPD that XRPD figure is substantially similar in Figure 56 schemes.In certain embodiments, crystal form B comprises the x-ray powder diagram of characteristic peak as shown in the top in Figure 56 or bottom pattern represented with the 2 θ number of degrees.

Moor that for Buddhist nun/Ketohexamethylene 1: 1 solvate crystalline B and that feature for Buddhist nun/2-methyl THF1: 0.4 solvate crystalline B of pool.

Figure 57 shows the XRPD figure of two other category-B forms and comparing of the XRPD figure obtained crystal form A.Top pattern obtains GEN8.1, described GEN8.1 be 1: 0.4 pool that for Buddhist nun/2-methyl THF solvate (category-B, lyophilization, solvent=2-methyl THF).Middle pattern obtains QSA7.1, described QSA7.1 be 1: 1 pool that for Buddhist nun/cyclohexanone solvent compound (category-B, solvent=Ketohexamethylene).Bottom pattern is the pattern obtained anhydrate crystal form A.

In the top XRPD figure shown in Figure 57, moor that at least one or all following peak for Buddhist nun/2-methyl THF solvate with 2 θ number of degrees display crystal form Bs 1: 0.4: 5.6; 9.5; 10.5; 11.2; 12.0; 12.5; 13.5; 14.0; 15.0; 15.5; 16.2; 16.8; 17.0; 18.1; 18.8; 20.1; 21.2; 22.1; 26.0; 26.1; 27.5; With 28.2.In certain embodiments, crystal form B 1: 0.4 is moored that feature for Buddhist nun/2-methyl THF solvate and is that XRPD figure comprises one or more following peak 2 θ: 5.6; 12.0; 14.0; 15.0; 15.5; 16.8; 18.1; 20.1; With 26.0.In the top XRPD figure shown in Figure 57, moor that at least one or all following peak for Buddhist nun/2-methyl THF solvate with 2 θ number of degrees display crystal form Bs 1: 0.4: 5.6; 12.0; 14.0; 20.1; 22.1 and 26.0.In certain embodiments, crystal form B 1: 0.4 is moored that feature for Buddhist nun/2-methyl THF solvate and is that XRPD figure comprises one or more following peak 2 θ: 5.6; 14.0; 20.1; With 26.0.In certain embodiments, that XRPD figure for Buddhist nun/2-methyl THF solvate of crystal form B 1: 0.4 pool shows two peaks being selected from above those peaks provided, three peaks, four peaks or five peaks.In certain embodiments, crystal form B 1: 0.4 is moored that feature for Buddhist nun/2-methyl THF solvate and is that the top XRPD that XRPD figure is substantially similar in Figure 57 schemes.In certain embodiments, crystal form B comprises the x-ray powder diagram of characteristic peak as shown in the top pattern in Figure 57 represented with the 2 θ number of degrees.

In the middle XRPD figure shown in Figure 57, moor that at least one or all following peak for Buddhist nun/cyclohexanone solvent compound with 2 θ number of degrees display crystal form Bs 1: 1: 5.6; 9.5; 11.0; 12.0; 12.9; 14.0; 15.2; 16.2; 16.8; 17.0; 18.1; 18.8; 19.5; 20.1; 21.8; 22.3; 23.0; 24.5; 26.1; 27.5; 28.0; With 28.2.In certain embodiments, crystal form B 1: 1 is moored that feature for Buddhist nun/cyclohexanone solvent compound and is that XRPD figure comprises one or more following peak 2 θ: 5.6; 11.0; 12.0; 12.9; 14.0; 15.2; 16.8; 18.1; 18.8; 20.1; 21.8; 22.3; 24.5; With 26.1.In the middle XRPD figure shown in Figure 57, moor that at least one or all following peak for Buddhist nun/cyclohexanone solvent compound with 2 θ number of degrees display crystal form Bs 1: 1: 5.6; 14.0; 15.2; 16.8; 20.1; 21.8; 22.3; With 26.1.In certain embodiments, crystal form B 1: 1 is moored that feature for Buddhist nun/cyclohexanone solvent compound and is that XRPD figure comprises one or more following peak 2 θ: 5.6; 14.0; 15.2; 16.8; 20.1; 22.3; With 26.1.In certain embodiments, that XRPD figure for Buddhist nun/cyclohexanone solvent compound of crystal form B 1: 1 pool shows two peaks being selected from above those peaks provided, three peaks, four peaks or five peaks.In certain embodiments, crystal form B 1: 1 is moored that feature for Buddhist nun/cyclohexanone solvent compound and is that XRPD figure is substantially similar to the middle XRPD figure in Figure 57.In certain embodiments, crystal form B comprises the x-ray powder diagram of characteristic peak as shown in the middle pattern in Figure 57 represented with the 2 θ number of degrees.

Figure 58 moors that DSC curve obtained for Buddhist nun/cyclohexanone solvent compound (QSA7.1) to category-B 1: 1, and its display endothermic event is at T _{peak value}=110.1 DEG C and T _{peak value}=198.6 DEG C of places.

Figure 59 is the figure that display category-B 1: 1 moors that replaces TGA and the SDTA Thermogram of Buddhist nun/cyclohexanone solvent compound (QSA7.1).

Those TGMS data for Buddhist nun/cyclohexanone solvent compound (QSA7.1) of category-B 1: 1 pool are presented in temperature interval 50-160 DEG C and 160-210 DEG C and mass loss 14.8% (Ketohexamethylene and water) and 0.2% (Ketohexamethylene) occur respectively.Mooring that for Buddhist nun/Ketohexamethylene ratio according to TGMS data assessment is about 1.0/0.96.

Use HPLC to carry out measuring category-B 1: 1 and moor the experiment that replaces the purity of Buddhist nun/cyclohexanone solvent compound (QSA7.1).According to HPLC, measuring that purity for Buddhist nun/cyclohexanone solvent compound (QSA7.1) of category-B 1: 1 pool is 99.7460% (area percentage).

Figure 60 moors that DSC curve obtained for Buddhist nun/2-methyl THF solvate (GEN8.1) to category-B 1: 0.4, and its display endothermic event is at T _{peak value}=67.1 DEG C and T _{peak value}=197.5 DEG C of places.

Figure 61 is the figure that display category-B 1: 0.4 moors that replaces TGA and the SDTA Thermogram of Buddhist nun/2-methyl THF solvate (GEN8.1).

Category-B 1: 0.4 is moored that and is presented at temperature interval 40-90 DEG C for TGMS data of Buddhist nun/2-methyl THF solvate (GEN8.1), mass loss 3.1% (2-methyl THF), 1.9% and 1.0% (2-methyl THF) occurs respectively in 90-165 DEG C and 165-215 DEG C.Mooring that for Buddhist nun/2-methyl THF ratio according to TGMS data assessment is about 1.0/0.4.

Use HPLC to carry out measuring category-B 1: 0.4 and moor the experiment that replaces the purity of Buddhist nun/2-methyl THF solvate (GEN8.1).According to HPLC, measuring that purity for Buddhist nun/2-methyl THF solvate (GEN8.1) of category-B 1: 0.4 pool is 99.5939% (area percentage).

moor the feature that replaces Buddhist nun crystal form C (low crystallization) polymorph

In as the methanol of solvent, low crystal form C can be obtained from crystal form A in slurry experiment.Find that crystal form C contains solvation methanol to moor that ratio about 1: 0.2 for Buddhist nun/methanol.

Figure 62 is the DSC curve obtained low crystal form C (GEN3.1), and its display endothermic event is at T _{peak value}=95.9 DEG C of places, exothermal event is at T _{peak value}=135.3 DEG C of places, and endothermic event is at T _{peak value}=198.1 DEG C of places.

Figure 63 is the figure of TGA and the SDTA Thermogram of the low crystal form C of display (GEN3.1).

The TGMS data of crystal form C (GEN3.1) are presented in the 40-150C of temperature interval and mass loss 1.3% (methanol) occur.Mooring that for Buddhist nun/methanol ratio according to TGMS data assessment is about 1.0/0.2.

Crystal form C is analyzed by X-ray powder diffraction (XRPD).Figure 64 shows the XRPD figure of the XRPD superposition of initial substance crystal form A (bottom pattern) and low crystal form C (top pattern).

In the top XRPD figure shown in Figure 64, at least one or all following peaks with 2 θ number of degrees display crystal form C: 3.2; 11.1; 11.7; 12.8; 13.3; 13.5; 14.2; 17.1; 18.2; 20.8; 22.3; With 26.5.In certain embodiments, the feature of crystal form C is that XRPD figure comprises one or more following peak 2 θ: 3.2; 12.8; 14.2; 17.1; 18.2; 20.8; 22.3 and 26.5.In the XRPD figure shown in Figure 64, at least one or all following peaks with 2 θ number of degrees display crystal form C: 3.2; 12.8; 14.2; With 18.2.In certain embodiments, the XRPD figure of crystal form C shows two peaks being selected from above those peaks provided, three peaks, four peaks or five peaks.In certain embodiments, the feature of crystal form C is that the top XRPD that XRPD figure is substantially similar in Figure 64 schemes.In certain embodiments, crystal form C comprises the x-ray powder diagram of characteristic peak as shown in Figure 64 represented with the 2 θ number of degrees.

HPLC is used to carry out the experiment of the purity measuring crystal form C (GEN3.1).

According to HPLC, measuring that purity for the crystal form C of Buddhist nun of pool is 99.5725% (area percentage).

moor the feature that replaces Buddhist nun crystal form D polymorph

In N,N-dimethylacetamide (DMA), collision crystallization is carried out from crystal form A acquisition crystal form D by adding anti-solvent.Find that the crystal form D produced in this way is that DMA solvate for the ratio about 1: 1 of Buddhist nun/DMA of pool.

Figure 65 is the DSC curve obtained crystal form D (GEN5.1R1), and its display endothermic event is at T _{peak value}=103.3 DEG C, T _{peak value}=125.6 DEG C and T _{peak value}=198.4 DEG C of places.

Figure 66 is the figure of TGA and the SDTA Thermogram of the low crystal form D of display (GEN5.1R1).

The TGMS data of crystal form D (GEN5.1R1) are presented in temperature interval 40-140 DEG C and mass loss 13.8% (N,N-dimethylacetamide) occur.Mooring that for Buddhist nun/DMA ratio according to TGMS data assessment is about 1.0/0.98.

Crystal form D is analyzed by X-ray powder diffraction (XRPD).Figure 67 shows XRPD figure (from bottom to top) of the XRPD superposition of following thing: initial substance crystal form A; Crystal form D (GEN5.1R1); And measuring again (GEN5.1R4) after 3 days, the sample analyzed whereby may contain category-B form and crystal form D.

In the middle XRPD figure shown in Figure 67, at least one or all following peaks with 2 θ number of degrees display crystal form D: 6.2; 8.0; 10.8; 11.5; 12.4; 13.5; 13.8; 14.5; 15.6; 16.5; 17.6; 18.5; 19.3; 19.8; 20.1; 20.8; 21.6; 22.1; 23.8; 26.0; 27.1; With 29.6.In certain embodiments, the feature of crystal form D is that XRPD figure comprises one or more following peak 2 θ: 6.2; 10.8; 12.4; 13.8; 14.5; 15.6; 16.5; 18.5; 20.2; 20.8; 21.6; 26.0; With 27.1.In the middle XRPD figure shown in Figure 67, at least one or all following peaks with 2 θ number of degrees display crystal form D: 6.2; 12.4; 14.5; 15.6; 16.5; 18.5; 20.2; 20.8; 21.6; 26.0; With 27.1.In certain embodiments, the feature of crystal form D is that XRPD figure comprises one or more following peak 2 θ: 6.2; 15.6; 16.5; 18.5; 20.2; 21.6; 26.0; With 27.1.In certain embodiments, the XRPD figure of crystal form D shows two peaks being selected from above those peaks provided, three peaks, four peaks or five peaks.In certain embodiments, moor that feature for the crystal form D of Buddhist nun and be that XRPD figure is substantially similar to the middle XRPD figure in Figure 67.In certain embodiments, crystal form D comprises the characteristic peak x-ray powder diagram as shown in figure 67 represented with the 2 θ number of degrees.

HPLC is used to carry out the experiment of the purity measuring crystal form D.According to HPLC, measuring that purity for the crystal form D of Buddhist nun of pool is 99.5056% (area percentage).

moor the feature that replaces Buddhist nun crystal form E (E class) polymorph

In pulp and solubility experiment, use as the solvent of oxolane (THF), chloroform and dichloromethane (DCM), or spread on solid by steam and prepare E kind solvent from crystal form A or low crystal form C.

Based on thermal analyses, the sample representing crystal form E be appointed as pool that for Buddhist nun/oxolane (THF) 1: 1 solvation form.Represent another sample seemingly chloroform solvate of crystal form E, but do not characterize this material further by the mode except XRPD.

Figure 68 moors that DSC curve obtained for Buddhist nun/THF1: 1 solvate (GEN7.1) to E class, and its display endothermic event is at T _{peak value}=95.9 DEG C and T _{peak value}=198.1 DEG C of places.

Figure 69 is that display E class moors the figure that replaces TGA and the SDTA Thermogram of Buddhist nun/THF1: 1 solvate (GEN7.1).

E class is moored that and is presented in temperature interval 40-130 DEG C for TGMS data of Buddhist nun/THF1: 1 solvate (GEN7.1) mass loss 11.7% (THF) occurs.Mooring that for Buddhist nun/THF ratio according to TGMS data assessment is about 1.0/0.98.

Two or more classification E polymorph mentioned is analyzed by X-ray powder diffraction (XRPD).Figure 70 shows XRPD figure (from bottom to top) of the XRPD superposition of following thing: initial substance crystal form A; E class moors that for Buddhist nun/THF1: 1 solvate (GEN7.1); That is moored for Buddhist nun/chloroform solvate (SLP3.1) with E class.

In the top XRPD figure shown in Figure 70, moor that at least one or all following peak for Buddhist nun/THF1: 1 solvate (GEN7.1) with 2 θ number of degrees display E classes: 6.2; 7.0; 10.0; 13.0; 15.1; 16.4; 17.2; 18.5; 20.4; 20.5; 22.5; 24.4; 25.6; With 27.0.In certain embodiments, E class is moored that feature for Buddhist nun/THF1: 1 solvate (GEN7.1) and is that XRPD figure comprises one or more following peak 2 θ: 6.2; 7.0; 10.0; 15.1; 16.4; 17.2; 18.5; 20.4; 20.524.4; With 27.0.In the top XRPD figure shown in Figure 70, moor that at least one or all following peak for Buddhist nun/THF1: 1 solvate (GEN7.1) with 2 θ number of degrees display E classes: 6.2; 15.1; 16.4; 17.2; 18.5; 20.4; 24.4; With 27.0.In certain embodiments, E class is moored that feature for Buddhist nun/THF1: 1 solvate (GEN7.1) and is that XRPD figure comprises one or more following peak 2 θ: 6.2; 15.1; 16.4; 20.4; With 20.5.In certain embodiments, E class is moored that and is shown two peaks being selected from above those peaks provided, three peaks, four peaks or five peaks for XRPD figure of Buddhist nun/THF1: 1 solvate (GEN7.1).In certain embodiments, E class is moored that feature for Buddhist nun/THF1: 1 solvate and is that the top XRPD that XRPD figure is substantially similar in Figure 70 schemes.In certain embodiments, crystal form E comprises the x-ray powder diagram of characteristic peak as shown in the top pattern in Figure 70 represented with the 2 θ number of degrees.

In the middle XRPD figure shown in Figure 70, moor that at least one or all following peak for Buddhist nun/chloroform solvate (SLP3.1) with 2 θ number of degrees display E classes: 6.2; 7.0; 8.7; 9.8; 12.1; 12.5; 13.0; 15.2; 16.4; 17.2; 18.5; 20.0; 21.0; 23.0; 24.4; 25.0; With 26.2.In certain embodiments, E class is moored that feature for Buddhist nun/chloroform solvate (SLP3.1) and is that XRPD figure comprises one or more following peak 2 θ: 6.2; 7.0; 13.0; 15.2; 16.4; 17.2; 18.5; 20.0; 21.0; 24.4; 25.0; With 26.2.In certain embodiments, E class is moored that and is shown two peaks being selected from above those peaks provided, three peaks, four peaks or five peaks for XRPD figure of Buddhist nun/chloroform solvate (SLP3.1).In certain embodiments, E class is moored that feature for Buddhist nun/chloroform solvate and is that XRPD figure is substantially similar to the middle XRPD figure in Figure 70.In certain embodiments, crystal form E comprises the x-ray powder diagram of characteristic peak as shown in the middle pattern in Figure 70 represented with the 2 θ number of degrees.

Use HPLC to carry out measuring E class and moor the experiment that replaces the purity of Buddhist nun/THF1: 1 solvate (GEN7.1).According to HPLC, it is 99.5120% (area percentage) that E class for Buddhist nun of mensuration pool moors that purity for Buddhist nun/THF1: 1 solvate (GEN7.1).

moor the feature that replaces Buddhist nun crystal form F polymorph

Under specific condition of experiment, as formed crystal form F from crystal form A in the presence of a polar solvent.By TGMS to the water of the analysis display crystal form F of crystal form F in the first temperature range 25-140 DEG C internal loss 3.3%.According to these results, the first endothermic event of observing of deducibility corresponds to dehydration, and crystal form F is hydrated form, such as, with 1: 1 hydrate of water.

According to screening experiment, store at ambient temperature after 4 months, by the selected sample of the XRPD mixture (6 samples) of analytical pure crystal form F (6 samples) and crystal form A and F again.The results are shown in following table 24.

table 24: the pure crystal form F analyzed again by XRPD after storage 4 months and crystal form the sample of the mixture of A+F.

^aas after completing crystallization experiment by XRPD classify.

^bcrystallisation mode: cool-evaporation (PSM), add collision crystallization (AS), the pulp (SLP) of anti-solvent, steam spreads (VDS) on solid and steam spreads (VDL) in solution.

^caccording to screening, select some experiments to store 4 months at ambient temperature and measured again by XRPD afterwards.

^das after stored sample at ambient conditions 4 months by XRPD classify.

Result in table 24 is presented in most cases, and polymorphic forms remains unchanged.The result display obtained in the collision crystallization experiment undertaken by anti-solvent (2-methyl cellosolve/water) is when wet method collects sample, and after 4 months, the crystal form F Substance Transformation of acquisition becomes crystal form A.In addition, add in experiment in the anti-solvent of being undertaken by acetone/water, after 4 months, crystal form F changes into the mixture of crystal form A and F.

TGA and the SDTA figure that Figure 71 display obtains crystal form F (AS16.2).Crystal form F (AS16.2) shows the first heat absorption, succeeded by recrystallization in temperature range 130-140 DEG C.Observe the fusing point of crystal form F (AS16.2) at about 189 DEG C of places.

As mentioned, the TGMS data of crystal form F (AS16.2) are presented in temperature interval 25-140 DEG C and mass loss 3.3% (water) occur.According to the pool of TGMS data assessment crystal form F, that is about 1.0/1.01 for Buddhist nun/water ratio.

Crystal form F (SLP10.1) is analyzed by X-ray powder diffraction (XRPD).In Figure 83, to be arranged under the overlay the many XRDP patterns of display, and wherein the pattern of crystal form F (SLP10.1) is the 5th pattern started from top.Use 1,2-dimethoxy-ethane as solvent, in slurry experiment, obtain this sample (SLP10.1).

Be shown as in the XRPD figure of the 5th pattern started from top in Figure 83, with 2 θ number of degrees display pool those at least one or all following peaks for Buddhist nun crystal form F: 7.2; 13.2; 14.1; 15.9; 18.1; 20.4; 21.1; 22.0; 23.5; 24.2; 25.5; With 26.8.In certain embodiments, the feature of crystal form F is that XRPD figure comprises one or more following peak 2 θ: 7.2; 13.2; 14.1; 15.9; 18.1; 20.4; 23.5; 25.5 and 26.8.Be shown as in the XRPD figure of the 5th pattern started from top in Figure 83, at least one or all following peaks with 2 θ number of degrees display crystal form F: 7.2; 14.1; 18.1; 20.4; 25.5; With 26.8.In certain embodiments, the XRPD figure of crystal form F shows two peaks being selected from above those peaks provided, three peaks, four peaks or five peaks.In certain embodiments, moor that feature for Buddhist nun crystal form F and be that XRPD figure is substantially similar to the 5th the XRPD figure started from top in Figure 83.In certain embodiments, crystal form F comprises the characteristic peak that represents with the 2 θ number of degrees x-ray powder diagram as shown in the 5th pattern started from top in Figure 83.

moor the feature that replaces Buddhist nun's form H (H class) polymorph

Moor the feature that replaces Buddhist nun/1-propanol 1: 1 solvate crystalline H

The solid that the dissolution experiment that personal 1-propanol carries out reclaims is confirmed as the 1-propanol solvate of form H.

That DSC curve display endothermic event obtained for Buddhist nun/1-propanol solvate (SAS35) is moored to H class and appears at T _{peak value}about 93 DEG C and T _{peak value}about 192 DEG C of places.

H class is moored that and is presented in temperature interval 25-120 DEG C for TGMS data of Buddhist nun/1-propanol solvate (SAS35) mass loss 9.2% (1-propanol) occurs.That replaces Buddhist nun/1-propanol ratio to be about 1.0/0.9 to moor that pool for Buddhist nun/1-propanol solvate (SAS35) according to TGMS data assessment H class.Another sample (SAS30) display corresponds to the mass loss of 1: 0.6 solvate, but this sample is determined that Partial Conversion returns exsiccation thing crystal form A subsequently, therefore makes the bulk solvent loss to gross sample is observed reduce.

H kind solvent compound (SAS35) is analyzed, at least one or all following peaks that wherein occur representing with the 2 θ number of degrees: 6.1 by X-ray powder diffraction (XRPD); 6.8; 10.0; 12.0; 13.2; 13.5; 16.0; 16.5; 16.0; 16.5; 18.0; 19.0; 19.5; 20.4; 21.0; 22.5; 25.0; 25.5; 26.2; 27.0; With 27.5.In certain embodiments, the feature of form H is that XRPD figure comprises one or more following peak 2 θ: 12.0; 13.2; 13.5; 18.0; 25.0 and 25.5.In certain embodiments, the XRPD figure of form H shows two peaks being selected from above those peaks provided, three peaks, four peaks or five peaks.

Moor the feature that replaces Buddhist nun/2-methyl cellosolve 1: 1 solvate crystalline H

Moor that can form form H in other alcohol isomorphism solvate for Buddhist nun's free alkali.Start as initial substance with crystal form A, and use 2-methyl cellosolve as solvent, obtain 2-methyl cellosolve solvate by steam to diffusion process in liquid.The purity assessing this form is 98.0%.TGMS confirm it be 1: 0.93 pool that for Buddhist nun/2-methyl cellosolve solvate, its desolventizing at about 96 DEG C.After desolvation, observe fusing point about 198.8 DEG C in DSC, this corresponds to the fusing point of crystal form A closely.

DVS experiment be presented at desorbing during the loss in weight about 3.6%, this until 45%RH adsorption cycle between do not regain.The XRPD carried out at the end of DVS experiment analyzes instruction without physical change.Although possible generating portion desolvation, process does not cause crystal structure to subside (as indicated in observed the loss in weight about 12% during desolvation by TG-MS).

But, store 10 months periods at ambient conditions, and in humidity chamber under accelerated stress condition (40 DEG C, 75%RH) after 1 week, form H changes into crystal form A.

Figure 72 is the DSC curve obtained form H (VLD1, the solid from liquid storage drying), and its display endothermic event is at T _{peak value}=96.1 DEG C (desolvation events) and T _{peak value}=198.8 DEG C of places.Suspect that the endothermic event located at 198.8 DEG C is the melting event of crystal form A.

The DVS experiment of form H (VLD1, the solid from liquid storage drying) is presented at the loss in weight about 11.7% (2-methyl cellosolve) in temperature range 25-120 DEG C.According to these results, the first endothermic event observed corresponds to desolvation process, and form H (VLD1, the solid from liquid storage drying) be 1: 0.93 pool that for Buddhist nun/2-methyl cellosolve solvate.

Figure 74 presents the XRPD to mooring that a series of XRPD figure replacing the various samples of form H of Buddhist nun to obtain and crystal form A.In Figure 74: Fig. 1 is form H (VLD2 tests, after 2 weeks and drying); Fig. 2 is form H (VLD1 tests, after 2 weeks and drying); Fig. 3 is form H (VLD1 tests, from the solid of liquid storage drying, after DVS); Fig. 4 is form H (VLD1, the solid from liquid storage drying); Fig. 5 is form H (VLD19); And base map is the XRPD of crystal form A.The XRPD figure being shown as Fig. 1-5 is similar substantially.

Be shown as in the XRPD figure of Fig. 5 in Figure 74, with 2 θ number of degrees display pool those at least one or all following peaks for Buddhist nun's form H: 6.2; 6.5; 10.1; 12.0; 13.2; 15.0; 15.5; 16.0; 16.5; 18.0; 19.1; 19.6; 20.5; 21.1; 23.0; 23.7; With 25.5.In certain embodiments, the feature of form H is that XRPD figure comprises one or more following peak 2 θ: 6.2; 12.0; 13.2; 16.0; 18.0; 19.1; 19.6; 20.5; 21.1; 23.0; With 25.5.Be shown as in the XRPD figure of Fig. 5 in Figure 74, at least one or all following peaks with 2 θ number of degrees display form Hs: 6.2; 12.0; 18.0; With 25.5.In certain embodiments, the XRPD figure of form H shows two peaks being selected from those peaks above, three peaks, four peaks or five peaks.In certain embodiments, moor that for feature of Buddhist nun's form H be in the pattern 1-5 that XRPD figure is substantially similar in Figure 74 any one.In certain embodiments, form H comprises the x-ray powder diagram of characteristic peak as shown in any one in the pattern 1-5 in Figure 74 represented with the 2 θ number of degrees.

HPLC is used to carry out the experiment of the purity measuring form H (VLD1, the solid from liquid storage drying).According to HPLC, measuring that purity for the form H (VLD1, the solid from liquid storage drying) of Buddhist nun of pool is 98.0464% (area percentage).

Figure 75 is overlapping with the FT-IR spectrum (Fig. 2) obtained the crystal form A characteristic FT-IR spectrum (Fig. 1) by mooring that form H (VLD1, dry from liquid storage) for Buddhist nun and obtaining.Percent transmission (%) shows on the vertical axis, and wave number (cm ^-1) display on the horizontal axis.

Figure 76 is overlapping with the FT-IR spectrum (Fig. 2 :) obtained the crystal form A characteristic FT-IR spectrum (Fig. 1) by mooring that form H (VLD1, dry from liquid storage) for Buddhist nun and obtaining, for the region of wavelength 1750-600nm.Percent transmission (%) shows on the vertical axis, and wave number (cm ^-1) display on the horizontal axis.These superposition qualification some characteristic peaks of form H and some characteristic peaks of crystal form A.Thus, in Figure 76 (Fig. 2), some characteristic peaks of crystal form A comprise: 1605; 1415; 1295; 1250; 1150; 1145; 1110; 1100; 895; 855; And 790cm ^-1.

moor the feature that replaces the low crystalline polymorph of Buddhist nun's crystalline form I

In dichloromethane (DCM), low crystalline form I is obtained by Freeze Drying Technique.

Based on thermal analyses, crystalline form I (GEN9.1) the solvation DCM containing small level, that replaces Buddhist nun/DCM ratio about 1: 0.03 to correspond to pool.

Figure 77 is the DSC curve obtained crystalline form I (GEN9.1), and its display exothermal event is at T _{peak value}=100.1 DEG C of places, and endothermic event is at T _{peak value}=196.7 DEG C of places.

Figure 78 is the figure of TGA and the SDTA Thermogram of display crystalline form I (GEN9.1).

The TGMS data of crystalline form I (GEN9.1) are presented in temperature interval 40-175 DEG C and occur mass loss 0.5% (DCM) (slightly solvation).Mooring that for Buddhist nun/DCM ratio according to TGMS data assessment is about 1.0/0.03.

Crystalline form I (GEN9.1) is analyzed by X-ray powder diffraction (XRPD).Figure 77 shows XRPD superposition (from bottom to top) of initial substance crystal form A and crystalline form I (GEN9.1).

In the top XRPD figure shown in Figure 79, at least one or all following peaks with 2 θ number of degrees display crystalline form I (GEN9.1): 6.5; 8.2; 9.8; 14.3; 15.5; 17.5; 21.2; 23.1; With 26.5.In certain embodiments, the feature of crystalline form I (GEN9.1) is that XRPD figure comprises one or more following peak 2 θ: 6.5; 8.2; 9.8; 14.3; 15.5; 17.5; 21.2; With 26.5.In the top XRPD figure of Figure 79, at least one or all following peaks with 2 θ number of degrees display crystalline form I (GEN9.1): 6.5; 8.2; 15.5; 17.5; 21.2; With 26.5.In certain embodiments, the feature of crystalline form I (GEN9.1) is that XRPD figure comprises one or more following peak 2 θ: 8.2; With 15.5.In certain embodiments, the XRPD figure of crystalline form I (GEN9.1) shows two peaks being selected from above those peaks provided, three peaks, four peaks or five peaks.In certain embodiments, moor that feature for Buddhist nun's crystalline form I and be that XRPD figure is substantially similar to the top pattern in Figure 79.In certain embodiments, crystalline form I comprises the x-ray powder diagram of characteristic peak as shown in the top pattern in Figure 79 represented with the 2 θ number of degrees.

HPLC is used to carry out the experiment of the purity measuring crystalline form I (GEN9.1).According to HPLC, measuring that purity for the crystalline form I (GEN9.1) of Buddhist nun of pool is 99.5802% (area percentage).

moor the feature that replaces Buddhist nun crystal form J polymorph

Crystal form J is obtained to method of diffusion on solid by steam.Assessment purity is 96.5%.TGMS analyzes (interval 25-130 DEG C period the loss in weight 11.4% thiophene) confirm crystal form J " low crystallization " be 1: 0.82 pool that for Buddhist nun/thiophene solvate, its desolventizing at 83.7 DEG C.After desolvation, fusing point event occurs in about 197.3 DEG C of places, and this can be the melting of crystal form A.

The loss in weight about 1.3% during DVS experiment is presented at desorbing.At least until during the adsorption cycle of 45% relative humidity (RH), weight seems not regained (mass absorption about 0.33%).The XRPD carried out at the end of DVS experiment analyzes indicator substance and changes into crystal form A.

After storing 10 months at ambient conditions, and under stress condition (40 DEG C, 75%RH) after 1 week, low crystal form J also changes into crystal form A.

Those two samples for Buddhist nun crystal form J of pool (being appointed as the VDS10 of VDS2 and screening S10010A) are analyzed by X-ray powder diffraction (XRPD).Figure 78 shows XRPD and superposes sample (from top to bottom): Fig. 6 is the XRPD figure of crystal form A (VDS2, after stability study); Fig. 7 is the XRPD figure of crystal form J (VDS2); Fig. 8 is the XRPD figure (VDS10 of screening S10010A) of crystal form J; And Fig. 9 is that another XRPD for Buddhist nun's crystal form A of pool to scheme.

In the XRPD Fig. 7 and 8 shown in Figure 80, show at least one or all following peaks of mooring those crystal form J for Buddhist nun with the 2 θ number of degrees: 5.8; 7.0; 12.1; 15.1; 16.8; 18.1; 18.6; 19.1; 19.5; 20.1; 21.1; 21.8; 22.8; 25.0; 25.7; With 27.0.In certain embodiments, moor that feature for the crystal form J of Buddhist nun and be that XRPD figure comprises one or more following peak 2 θ: 5.8; 7.0; 12.1; 15.1; 16.8; 18.1; 19.1; 19.5; 20.1; 21.1; 21.8; 22.8; 25.0; 25.7; With 27.0.In the top XRPD figure of Figure 80, show at least one or all following peaks of mooring those crystal form J for Buddhist nun with the 2 θ number of degrees: 5.8; 7.0; 12.1; 15.1; 16.8; 18.6; 19.1; 19.5; 21.8; 22.8; 25.0; 25.7; With 27.0.In certain embodiments, moor that feature for the crystal form J of Buddhist nun and be that XRPD figure comprises one or more following peak 2 θ: 5.8; 7.0; 12.1; 15.1; 18.6; 19.5; 21.8; 25.0; 25.7; With 27.0.In certain embodiments, moor that XRPD figure for the crystal form J of Buddhist nun and show two peaks being selected from above those peaks provided, three peaks, four peaks or five peaks.In certain embodiments, any one that feature of crystal form J for Buddhist nun is in Fig. 7 and 8 that XRPD figure is substantially similar in Figure 80 is moored.In certain embodiments, crystal form J comprises the x-ray powder diagram of characteristic peak as shown in any one in Fig. 7 in Figure 80 and 8 represented with the 2 θ number of degrees.

HPLC is used to carry out the experiment of the purity measuring crystal form J (VDS2).According to HPLC, measuring that purity for the crystal form J (VDS2) of Buddhist nun of pool is 96.4509% (area percentage).

Figure 81 is overlapping with the FT-IR spectrum (Fig. 2) obtained the crystal form A characteristic FT-IR spectrum (Fig. 1) by mooring that and obtaining for the crystal form J (VDS2) of Buddhist nun.Percent transmission (%) shows on the vertical axis, and wave number (cm ^-1) display on the horizontal axis.

Figure 82 is overlapping with the FT-IR spectrum (Fig. 2) obtained the crystal form A characteristic FT-IR spectrum (Fig. 1) by mooring that and obtaining for the crystal form J (VDS2) of Buddhist nun, for the region of wavelength 1750-600nm.Percent transmission (%) shows on the vertical axis, and wave number (cm ^-1) display on the horizontal axis.

moor the feature that replaces Buddhist nun crystal form K polymorph

Solid crystalline K sees in sample SAS58 (MSZW experiment): 25mg/mL is in 1-propanol/acetonitrile 30/70.TGMS Thermogram display mass loss before melting can be ignored (in temperature interval 25-175 DEG C < 0.04%).According to SDTA signal, the fusing point of crystal form K is 184 DEG C

T is appeared to that DSC curve display endothermic event obtained for Buddhist nun crystal form K of pool _{peak value}about 184 DEG C of places.

By X-ray powder diffraction (XRPD) analyze pool that for Buddhist nun crystal form K, at least one or all following peaks that wherein occur representing with the 2 θ number of degrees: 10.0; 11.0; 13.4; 14.6; 15.2; 16.0; 17.0; 17.5; 18.0; 19.6; 20.9; 22.1; 22.8; 24.1; 24.8; 26.5; 27.1; 28.5; With 30.5.In certain embodiments, the feature of crystal form K is that XRPD figure comprises one or more following peak 2 θ: 10.0; 11.0; 13.4; 14.6; 15.2; 16.0; 19.6; 20.9; 22.1; 22.8; 24.1; 24.8; With 26.5.In certain embodiments, the feature of crystal form K is that XRPD figure comprises one or more following peak 2 θ: 10.0; 11.0; 13.4; 14.6; 15.2; 19.6; 22.1; 22.8; With 24.1.In certain embodiments, the XRPD figure of crystal form K shows two peaks being selected from those peaks above, three peaks, four peaks or five peaks.

that superposition for the XRPD figure of Buddhist nun's polymorph of selected pool

Figure 83 is the superposition to that XRPD result obtained for Buddhist nun's free base polymorph thing of selected pool.From bottom to top, the XRPD figure of display obtains following thing: crystal form A (SM); Category-B (QSAS7.1); Crystal form C, low crystallization (GEN3.1); Crystal form D (GEN5.1); E class (SLP3.1); Crystal form F (SLP10.1); Crystal form G (AS19.1), discusses below in this article; Form H (VDL19.1); Crystalline form I, low crystallization (GEN9.1); With crystal form J, low crystallization (VDS10.1).

moor the feature that replaces Buddhist nun crystal form G polymorph

Figure 83 describes to moor that for Buddhist nun crystal form G, and it is obtained by collision crystallization/anti-solvent method, and the solvent wherein used is 3-methyl-1-butanol, and the anti-solvent used is cyclohexane extraction.By X-ray powder diffraction (XRPD) analyze pool that for Buddhist nun crystal form G, at least one or all following peaks that wherein occur representing with the 2 θ number of degrees: 5,0; 6.5; 9.5; 12.0; 12.5; 14.0; 15.0; 16.5; 17.2; 18.4; 20.0; 21.0; 22.8; 23.5; 24.6; With 29.5.In certain embodiments, the feature of crystal form G is that XRPD figure comprises one or more following peak 2 θ: 5.0; 6.5; 9.5; 14.0; 15.0; 16.5; 17.2; 18.4; 20.0; With 22.8.In certain embodiments, the feature of crystal form G is that XRPD figure comprises one or more following peak 2 θ: 5.0; 6.5; 9.5; 14.0; 17.2; 18.4; 20.0; With 22.8.In certain embodiments, the XRPD figure of crystal form G shows two peaks being selected from above those peaks provided, three peaks, four peaks or five peaks.In certain embodiments, moor that feature for the crystal form G of Buddhist nun and be that XRPD figure is substantially similar in Figure 83 from the 4th pattern that the top of superposition sample starts.In certain embodiments, crystal form G comprises the characteristic peak that represents with the 2 θ number of degrees x-ray powder diagram as shown in the 4th pattern started from top in Figure 83.

Embodiment 6

Find that polymorphic forms for Buddhist nun of pool

In order to find that initial trial for the polymorphic forms of Buddhist nun of pool is divided into two periods.3 phases related to initial substance sign, feasibility test and solubility studies and think that 4 phases solvents are selected to provide data.4 phases related to 192 polymorph screening experiment of carrying out under milliliter (ml) scale.These initially attempt causing finding those 11 kinds of polymorphic forms for Buddhist nun's free alkali of pool, i.e. crystal form A, crystal form B, crystal form C, crystal form D, crystal form E, crystal form F, crystal form G, form H, crystalline form I, crystal form J and crystal form K.

1 phase: initial substance characterizes

Obtain compound by the following synthesis discussed in this article and moor that for Buddhist nun's free alkali, the feature of described synthesis is the amide coupling reaction of amine subunit and methyl ester subunit.Obtain about 20 grams of free alkalis (combination is appointed as two batches of F09-05575 and F09-05576 certainly) in faint yellow solid shape.This initial substance is characterized by XRPD, digital image, DSC, TGMS and HPLC.

Figure 84 shows the XRPD figure of free alkali initial substance, and wherein two patterns represent above-mentioned two batches (F09-05575: bottom pattern; And F09-05576: top pattern).

Figure 85 is that DSC curve for Buddhist nun's free alkali initial substance batch F09-05575 of pool, and its display endothermic event is at T _{peak value}=182.6 DEG C and T _{peak value}=199.0 DEG C of (mainly) places.Main heat absorption corresponds to melting event, and this can with desolvation process (as observed in the TGA/SDTA trace of this batch).

Figure 86 is that DSC curve for Buddhist nun's free alkali initial substance batch F09-05576 of pool, and its display endothermic event is at T _{peak value}at=199.6 DEG C.Heat absorption corresponds to melting event, and this can with desolvation process (as observed in the TGA/SDTA trace of this batch).

Figure 87 is that figure for TGA and the SDTA Thermogram of Buddhist nun's free alkali initial substance batch F09-05575 of display pool.

Figure 88 is that figure for TGA and the SDTA Thermogram of Buddhist nun's free alkali initial substance batch F09-05576 of display pool.

TGA and TGMS analyzes a display batch F09-05575 and has single step mass loss (in temperature interval 25-210 DEG C 0.9%), and in batch F09-05576, observe two step mass losses (in temperature interval 25-120 DEG C mass loss 0.3% and in interval 120-210 DEG C 0.9%).The mass loss observed in two batches correspond to 2-methyltetrahydrofuran (as by the m/z ratio observed in MS data confirm).This solvent exists with residual volume can come from that last synthesis step for Buddhist nun's free alkali compound of pool.

HPLC is used to carry out in order to measure that experiment for the purity of Buddhist nun's free alkali compound of pool.According to HPLC, the purity measuring batch F09-05575 is 99.5166% (area percentage), and the purity of batch F09-05576 is 99.6869% (area percentage).

In various embodiments, the alternative method preparing crystal form A produces the different sample of crystallinity.

Substituting pool that for Buddhist nun's crystal form A free alkali preparation method

Preparation 1

Operate the M010578 sample of ABL411057 (2-Me-THF, 1.1 equivalent aniline, 1.6 equivalent KOtBu) from pure 1-propanol crystal from 180g, in pure acetonitrile, grind the moistening product of 1-PrQH subsequently to produce the crystal form A of 99.39a% purity.

Preparation 2

Obtain from the solution of M010578 in 1-PrOH two samples operating ABL411060 (2-Me-THF, 26 DEG C of IT, 1.1 equivalent aniline, 1.6 equivalent KOtBu) from 180g, described solution obtains after 2-Me-THF replaces to 1-PrOH at solvent.With 9: 1 segmentation 1-PrOH solution.

Make the 779.5g of M010578 in 1-PrOH (9 parts) above solution crystallised overnight at ambient temperature.After filtration, at 40 DEG C, in 160g acetonitrile, grind wet cake, filter also dry (50 DEG C, 3mbar) and moor that for Buddhist nun's free base form A (99.87a%) to obtain 211.6g.

Add 260g acetonitrile in 86.6g (1 part) the above solution of M010578 in 1-PrOH.Filter suspension after 1 hour, filter cake ACN/1-PrOH (3: 1v/v) washing, and drying is to obtain 25.6g free alkali (99.27a%).From 1-propanol crystal be separated, succeeded by grinding the HPLC purity of product of generation higher than the purity by carrying out being separated from the mixture precipitation of ACN/1-PrOH in acetonitrile.

1 phase: solubility studies

That carries out quantitative dissolubility test for Buddhist nun's free alkali initial substance to pool to adopt one group of 20 kinds of solvent.At the little prepared slarry at present of equilibration time 24, after this Filter slurry.Dissolubility is measured by saturated solution by HPLC.Residual solid is characterized by XRPD.Result is summarized in following table 25.

table 25:3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{ (4-methyl piperazine piperazine-1-base) methyl]-3-(trifluoromethyl) phenyl } solubility studies of Benzoylamide

Experiment	Solvent title	Dissolubility (mg/ml)	XRPD form ¹
				QSA1	Diethylene glycol ether	32.35	A
QSA2	Ether	0.95	A
				QSA3	Dimethyl sulfoxine	124.45	A
QSA4	Isobutyl isobutyrate	2.5	A
				QSA5	N,N-dimethylacetamide	OR ³	A
QSA6	Amyl ether	UR，＜0.21 ²	A
				QSA7	Ketohexamethylene	30.78	Category-B
QSA8	Xylol	0.8	A
				QSA9	Isobutanol	20.95	A
QSA10	Butyl acetate	8.04	A
				QSA11	Normal heptane	UR，＜0.21 ²	A
QSA12	Water	UR，＜0.21 ²	A
				QSA13	2,2,2-trifluoroethanol	OR ³	A
QSA14	Phenyl-hexafluoride	0.21	A
				QSA15	Isopropyl alcohol	11.23	A
QSA16	Isopropyl acetate	5.8	A
				QSA17	1,2-dichloroethanes	10.8	A
QSA18	Acetonitrile	1.53	A
				QSA19	Oxolane	146.17	A
QSA20	Methanol	42.95	A
				QSA21	Water	UR，＜0.21 ²	A
QSA22	Water	UR，＜0.21 ²	A
				QSA23	Normal heptane	UR，＜0.21 ²	A
QSA2.4	Normal heptane	UR，＜021 ²	A

Experiment	Solvent title	Dissolubility (mg/ml)	XRPD form ¹
				QSA27	Dimethyl sulfoxine	139.72	A
QSA28	Dimethyl sulfoxine	138.56	A
				QSA29	Acetonitrile	1.15	A
QSA30	Acetonitrile	1.38	A
				QSA31	2-methyltetrahydrofuran	35.5	A
QSA32	Ethanol	25.2	A

(1) based on the solid form that XRPD analysis and evaluation is obtained by serosity.

(2) lower than scope, lower than detectability, concentration is lower than 0.21mg/mL.

(3) overrun, substance dissolves, concentration is higher than 200mg/mL.

The polymorph identical with the initial substance free alkali being appointed as crystal form A by the material obtained in 19 times in assessing at 22 different solubilities.The solid carrying out the serosity that personal Ketohexamethylene obtains shows different XRPD, and it is designated as category-B form.Crystal form B is characterized by 4 kinds of solvates further, as above in this article discuss.

To that feasibility study for Buddhist nun's free alkali compound of pool

Carry out feasibility test to attempt to obtain the amorphous free base material that can be used in some crystallization techniques of 4 phases.Adopt two kinds of technology, i.e. grinding and lyophilization.Below present result.

Grinding.As in following table 26 summarize, under 30Hz frequency, carry out two grinding experiments by two various durations.After grinding 60 or 120 minutes, material keeps crystallization (crystal form A).

table 26: moor the grinding feasibility study that replaces Buddhist nun's free alkali.

Lyophilization.With pool, that carries out 8 lyophilization experiments for Buddhist nun's free alkali compound.These General description of experiments are in following table 27.

table 27:3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{ (4-methyl piperazine piperazine-1-base) methyl]-3-(trifluoromethyl) phenyl } lyophilization of benzamide monohydrochloride is feasible journal of Sex Research

(1) based on TGMS result; (2) by chemical purity that HPLC measures.

Under the solvent of such as 2,2,2-trifluoroethanols (TFE) and TFE/ aqueous mixtures, obtain amorphous substance.Be, in the experiment carried out in 2-methyltetrahydrofuran, DMA/ water (90: 10) and THF, to observe 3 kinds of novel crystalline form, and be appointed as category-B, D and E class.Category-B and E class form are also observed in the screening of 4 phases, and the result of described 4 phases screening shows that they are isomorphism structures.Be, in all the other experiments carried out in methanol and dichloromethane, to produce two kinds of low crystalline materials (being the low crystallization of crystal form C and the low crystallization of crystalline form I respectively).

Novel crystalline form is analyzed further to determine their feature by DSC, TGMS and HPLC.Crystal form D and crystal form E is accredited as solvate (being 1: 1API/DMA and 1: 1API/THF respectively).

The low crystalline material obtained from methanol (the low crystallization of C) and dichloromethane (the low crystallization of I) has limited amount residual solvent (be respectively in 40 DEG C-150 DEG C, temperature interval 1.3% and in 40 DEG C-175 DEG C, interval 0.5%).

Because the lyophilization program of carrying out in methanol is not the optimum selection producing low crystalline material, so select the program of carrying out in dichloromethane to produce this material for the cooling/evaporative crystallization of 4 phases and steam in diffusion experiment on solid.

Based on that feasibility study result for Buddhist nun's free alkali of pool and dissolubility property, select the solvent being used for the experiment of 4 phases.

Solvent is assessed

For selecting the concentration range of screening solvent and determining to be ready to use in screening, quantitative dissolubility test is carried out to free alkali initial substance batch F09-05575.This screening employing one group of 20 kinds of solvent.For each solvent, standard 1.8ml screw cap vial is feeded with 40mg initial substance, 200 μ l solvents and magnetic stirring bar.Then sealed vials, and 24 hours are under agitation balanced at 25 DEG C.Filter (0.5 micron) gained mixture (serosity), and the mother solution of separation is diluted to two dilution factors selected according to calibration trace.Analyze (DAD) by HPLC and measure the amount of API in dilute solution.Calibration trace is obtained by the liquid storage of two kinds of independent preparations of free alkali compound in 2,2,2-trifluoroethanol.

After solubility test, at ambient temperature under vacuo from each bottle (serosity) evaporate residual solvent.All gained residues are analyzed to measure novel crystalline form by X-ray powder diffraction.

Feasibility study

To the General conditions of the feasibility study of free alkali compound in following table 28.After experiment, carry out HPLC and analyze to measure purity, and carry out thermal analyses to measure the thermal characteristics of each form.

table 28: be applied to that condition for the feasibility study of Buddhist nun's free alkali compound of pool.

(1) by solvent that TGA assesses; (2) by purity that HPLC assesses

The design of polymorph screening experiment and scheme

192 kinds of different conditions are used under milliliter (ml) scale, to carry out mooring that polymorph screening experiment for Buddhist nun's free alkali compound, the wherein following 6 kinds of different crystallization procedure of application: cooling-evaporation, anti-solvent interpolation, grinding, pulp, steam spreads in solution and steam spreads on solid.

Cooling-evaporative crystallization is tested

Adopt 24 kinds of different solvents and a kind of concentration, in 8ml bottle, carry out 24 cooling-evaporation experiments under milliliter scale.In each bottle, 25mg is moored that and carries out liquid addition (with dichloromethane) for Buddhist nun's free alkali.Freeze drying example is to obtain the low crystalline material of powdery.Then, add screening solvent and be about 60mg/ml (seeing table 29) to reach concentration.Sealed vials, and Temperature Distribution is obtained as described in following table 30.Cooling mixture to 5 DEG C, and keep 48 hours at such a temperature, subsequently bottle is placed under vacuo.Evaporating solvent a couple of days under 200mbar or 10mbar, and analyzed by XRPD and digital image.

table 29: the experiment condition for 24mL experiment using cooling-method of evaporating.

Table 30: for the Temperature Distribution of (24) cooling-evaporation experiment.

Experiment	The rate of heat addition	T _Initially	Keep	Cooldown rate	T _Finally	Keep
							PSM1-24	10	60	60	1	5	48

Add the collision crystallization of anti-solvent

For collision crystallization experiment, use 23 kinds of different solvents anti-solvent different from 18 kinds (seeing table 31), apply 48 kinds of different crystallization conditions.For each solvent, prepare liquid storage, pool in every case that be the concentration obtained in the saturated condition at ambient temperature after 17 hours at the forward horizontal stand be filtered in one group of 8ml bottle for Buddhist nun's paper mill wastewater that dissociates.Use solvent and anti-solvent ratio 1: 0.25, to these bottles each in add different anti-solvent.Under there are not those situations precipitated wherein, this ratio is increased to 1: 4, the waiting time wherein between each interpolation is 60 minutes.By the solid precipitated in the centrifugal waiting time be separated between anti-solvent interpolation.If do not obtain solid, then at room temperature complete evaporating solvent under vacuo.If acquisition solid, then analyze them by XRPD and digital image.

table 31: the experimental design adding the collision crystallization experiment of anti-solvent.

Grinding experiment

Dropping grinding technique uses to be added into moors that for a small amount of solvent in Buddhist nun's free base material, and this material 2 stainless-steel grinding balls grind in stainless-steel grinding tank.In this way, the impact of 24 kinds of different solvents (seeing table 32) is probed into.Usually, grind and analyze 30mg initial substance.

table 32: for the experiment condition of grinding experiment

Experiment	Solvent	Weight (mg)	Volume (ul)
				GRP1	Phenyl-hexafluoride	28.6	10
GRP2	Cyclohexane extraction	31.0	10
				GRP3	Acetonitrile	30.2	10
GRP4	Ethylene glycol dimethyl ether	30.5	10
				GRP5	Diethoxymethane	29.7	10
GRP6	Normal heptane	30.4	10
				GRP7	Pure isooctane	30.1	10
GRP8	Water	29.7	10
				GRP9	Nitrocarbol.	29.9	10
GRP10	Isosorbide-5-Nitrae-diox	30.9	10
				GRP11	α, α, α-benzotrifluoride	29.5	10
GRP12	Toluene	29.7	10
				GRP13	2-nitropropane	29.9	10
GRP14	1-nitropropane	29.5	10

Experiment	Solvent	Weight (mg)	Volume (ul)
				GRP15	Xylol	30.7	10
GRP16	N octyl fluoride	29.6	10
				GRP17	Isoamyl acetate	24.1	10
GRP18	O-Dimethylbenzene	30.2	10
				GRP19	N-nonane	29.5	10
GRP20	Ketohexamethylene	30.6	10
				GRP21	Diethylene glycol-dimethyl ether	29.9	10
GRP22	Sec-butylbenzene	29.7	10
				GRP23	Decane	30.1	10
GRP24	(R)-(+)-limonene	29.4	10

Slurry experiment

With pool, that carries out total 48 slurry experiment for Buddhist nun's free alkali, 24 kinds of solvents for 2 weeks at 10 DEG C and 30 DEG C of respective lower continuing.Following table 33 summarizes experiment condition.Test by stirring the suspension of material in solvent at controlled.At the end of slurry time, bottle is centrifugal, and separating solids and mother solution.At room temperature further drying solid under perfect vacuum, and analyzed by XRPD and digital image.

table 33: for the experiment condition of slurry experiment

Steam spreads in solution

For diffusion of vapor experiment, that saturated solution for Buddhist nun's free alkali of pool is at room temperature made to be exposed to solvent vapo(u)r two weeks.The saturated solution of certain volume is transferred in unlimited 8ml bottle, and is placed in the airtight 40ml bottle with 2ml anti-solvent (seeing table 34).After the two weeks, the solid of sample for reference is formed.If there is solid, then liquid is made to be separated with solid.Drying sample under vacuum (200mbar or 10mbar), analyzes them by XRPD and digital image subsequently.

table 34: the experiment condition spread in solution for steam

Steam spreads on solid

For diffusion of vapor experiment, at room temperature make amorphous moor that and be exposed to solvent vapo(u)r two weeks for Buddhist nun's free alkali.By API liquid addition in 8ml bottle, then lyophilization.The 8ml bottle with amorphous substance is opened wide, and is placed in the airtight 40ml bottle with 2ml anti-solvent (seeing table 35).After the two weeks, solid is analyzed by XRPD and digital image.If solid is by steam liquefied, then drying sample under vacuum (200mbar or 10mbar), analyzes them by XRPD and digital image subsequently.

table 35: the experiment condition spread on solid for steam

That physical stability for Buddhist nun's polymorph of selected pool and expanding in proportion

The object of this research is to produce again and is characterized in that solid form for Buddhist nun of pool identified in the above research discussed in this article further.According to this research, determine that crystal form D (isomorphism solvate) and crystal form F (monohydrate) has physical stability period of at least 10 months at ambient conditions.The period of going through at ambient conditions 10 months from form and crystal form G, H, I (low crystallization) and the J (low crystallization) of category-B and E class changes into crystal form A.

Expansion form H and J (low crystallization) are successful in proportion.The scale-up trial of crystal form G produces crystal form A.Following interimly 3 time expand project in proportion:

1 phase: probe into by XRPD the various forms of physical stabilities obtained in previously research after storing 8-10 month at ambient conditions;

2 phases: that replaces solid form selected by Buddhist nun's free alkali to be extended to 50-120mg in proportion to characterize further by pool; And

3 phases: determine the Solvation State of the material from 2 phases, hot characteristic sum physical stability.

1 phase result

Crystal form D (isomorphism solvate) and crystal form F (monohydrate) is stable at the duration of research.The isomorphism solvate of crystal form B class and crystal form E class all changes into crystal form A.Crystal form G, H, I (low crystallization) and J (low crystallization) change into crystal form A.Figure 89 presents that general introduction of tabular for the physical stability of Buddhist nun's solid form of some pools.

2 phases: that replaces Buddhist nun's free alkali form to expand selected pool in proportion

Select crystal form G, H and J (low crystallization) for expanding test in proportion.Scale-up experiment condition takes from polymorph disclosed herein screening.Form H and J (low crystallization) are expanded in proportion by success.Figure 90 presents the tabular general introduction expanding the result of experiment in proportion of selected free alkali form.

3 phases: be characterized in the form obtained in expanding in proportion

Come in the following manner to be characterized in preceding epoch further and expand in proportion, and confirm the solid form of its form by XRPD: DSC, TGMS, FTIR, HPLC and DVS.Do not characterize further by the crystal form A attempting to expand in proportion crystal form G generation.In addition, the physical stability for accelerated ageing conditions (40 DEG C and next week of 75%RH) is probed into.Figure 91 is that general introduction of tabular for the various signs of Buddhist nun's free alkali form of the successful pool produced again under being presented on 120mg scale.

pharmaceutical composition and with its treatment physiology condition of illness

The disclosure provides pharmaceutical composition, and its hydrochloric acid disclosed herein comprising treatment effective dose moors that crystal form for Buddhist nun and the pharmaceutically acceptable carrier of at least one, vehicle or excipient.In certain embodiments, the unit dosage forms of pharmaceutical composition comprises hydrochloric acid and moors that for the single crystal form of Buddhist nun as API.Or the unit dosage forms of pharmaceutical composition comprises hydrochloric acid and moors more than one crystal forms that replaces Buddhist nun.In certain embodiments, exist in compositions about more than 50%, about more than 70%, about more than 80% or about more than 90% single crystal form be one in institute's preferred form of this.In any foregoing embodiments, a kind of or all crystals form is substantially pure.For example, in certain embodiments, pharmaceutical composition comprises hydrochloric acid and moors that for substantially pure crystal form A of Buddhist nun and the pharmaceutically acceptable carrier of at least one, vehicle or excipient.Or pharmaceutical composition comprises hydrochloric acid and moors that for crystal form A of Buddhist nun and crystal form J and the pharmaceutically acceptable carrier of at least one, vehicle or excipient.Other version of this theme will be easy to show for having benefited from those skilled in the art of the present disclosure and easily know.

The pharmaceutically acceptable carrier of at least one, diluent, vehicle or excipient can be easy to be selected by those of ordinary skill in the art, and will be determined by required mode of administration.The illustrative example of mode of administration be applicable to comprise oral administration, per nasal, through parenteral, through surface, percutaneous and per rectum.Pharmaceutical composition disclosed herein can be adopted as those skilled in the art and regard as applicable any medicament forms.The medicament forms be applicable to comprises solid, semisolid, liquid or lyophilized formulations, as tablet, powder, capsule, suppository, suspension, liposome and aerosol.

Moor that to moor those various solid forms for Buddhist nun for various solid form of Buddhist nun and hydrochloric acid and can be combined under treatment effective dose to needing the experimenter treated to use separately or with any.Similarly, pool disclosed herein that moor that any solid form for Buddhist nun for Buddhist nun and hydrochloric acid and all separately or can become to be used for the treatment of subsequently the pharmaceutical composition of various disease state of people or other animal with any formulated in combination.For example, comprise any single or combination pool that moor for Buddhist nun and/or hydrochloric acid CML or Ph+ALL that pharmaceutical composition for the polymorph of Buddhist nun all can be used for by treating described experimenter in need to the pharmaceutical composition of experimenter's administering therapeutic effective dose in need.

iII. synthesis is moored that and is moored that for Buddhist nun for Buddhist nun and hydrochloric acid

Moor that and moor that product synthesized for convergence four step that Buddhist nun is description in flow process 1 for Buddhist nun's free alkali and hydrochloric acid.Step 1 relates to synthesizes " methyl ester " intermediate A P25047 from initial substance AP24595, AP28141 and AP25570.Step 2 relates to synthesizes " aniline " intermediate A P24592 from initial substance AP29089.Step 3 is base catalysis AP25047 and to produce the pool that is separated with free alkali form, that replaces Buddhist nun's free alkali in AP24592 coupling, is also appointed as AP24534.Step 4 forms also crystallization in ethanol to moor the mono-hydrochloric salts that replaces Buddhist nun.

Hydrochloric acid is moored the representative route of synthesis of that one for Buddhist nun and is appointed as process C.

flow process 1: process C

Step 1: synthesis AP25047 (" methyl ester ") intermediate

General introduction and synthesis flow

Hydrochloric acid moor that for step 1 of Buddhist nun's method be with under not separation of intermediates (" intussusception " (telescoped)) carry out three reactions (being appointed as 1a, 1b and 1c) successively from initial substance AP24595, AP25570 and AP28141 synthesis methyl ester intermediate AP25047, as in flow process 1 describe.The arrangement of two aromatic ring systems connected by single alkynes joint is built in the basic conditions by the Sonogashira coupling of the palladium/copper catalysis of two series connection and the desilyated reaction of original position.Then rough AP25047 product is made to stand the series of processing steps being designed to remove residual mineral catalyst and process by-product.These operations comprise from non-polar solven toluene with hydrochloride form crystalline A P25047 (unit operations 1.3), aqueous treatment and plug of silica gel (unit operations 1.4) and from polar solvent 2-propanol crystal (unit operations 1.5).Twice crystallization is provided for repelling the orthogonal purification of the related substances impurity with opposed polarity.Hydrochlorate is controlled from the crystallization of toluene and solvent wash by analytical test in the process for particular procedure impurity.AP25047 intermediate has been made to stand multivariate DoE research to determine powerful design space of repelling other impurity being reacted generation by intussusception from the final crystallization of 2-propanol.In a series of 8 processes in step 1, test provides and repels reaction completeness, impurity and effectively remove the quantitative analysis control of residual solvent.

flow process 2: step 1-synthesizes AP25047

Unit operations 1.1: the 1Sonogashira reacts

By AP24595, tetra-triphenylphosphine palladium (Pd (PPh ₃) ₄), Hydro-Giene (Water Science). (I) (CuI), triethylamine and oxolane (THF) load in reactor.Stir the mixture, and with degas with nitrogen, then load AP28141 degassed in advance.Make gained mixture reach 45-55 DEG C, and keep being no less than 3 hours.Determine to react completeness by IPC-1 (HPLC).If meet IPC-1 standard, then mixture be concentrated into target volume and cool.

Unit operations 1.2: deprotection/the 2Sonogashira reacts

By AP25570, extra tetra-triphenylphosphine palladium (Pd (PPh ₃) ₄), Hydro-Giene (Water Science). (I) (CuI) and oxolane (THF) load in reactor.Enriched mixture, and measure water content by IPC-2 (KF).If meet IPC-2 standard, then make mixture be warming up to 45-60G, and slowly add the methanol solution of 25% Feldalat NM.Stirred reaction mixture, and 30-60 minute is kept at 45-55 DEG C.Reaction progress is determined by IPC-3 (HPLC).During IPC analyzes, reactant mixture can be made to keep at a lower temperature.If meet IPC-3 standard, then process is made to proceed to unit operations 1.3.

Unit operations 1.3: be separated hydrochloric acid AP25047

Under agitation, the reactant mixture of cancellation cooling is carried out by adding hydrogen chloride gas.Form precipitation, and remove remaining hydrogen chloride by nitrogen purge from suspension.Oxolane (THF) is replaced by under reduced pressure azeotropic distillation toluene.In agitation and filtration exsiccator, filter gained warm slurry, and grind and washing leaching cake with warm toluene.The content of Process Impurity AP29116 is measured by IPC-4 (HPLC).If meet IPC-4 standard, then under 35-45 DEG C (jacket temperature) under nitrogen current and decompression under agitation dry wet filter cake.Dry by IPC-5 (LOD, gravimetric analysis) monitoring.If meet IPC-5 standard, then discharge rough hydrochloric acid AP25047, and be packaged in the FEP bag in plastic containers.Before pre-treatment, the hydrochloric acid AP25047 be separated can be kept to reach 7 days.

Unit operations 1.4: process

Rough hydrochloric acid AP25047 solid is loaded in reactor together with dichloromethane (DCM), and washs with ammonia spirit.Reclaim object DCM strip aqueous for output, and the organic facies ammonia spirit merged washs again.Organic layer then washs until aqueous phase reaches pH1-2 with aqueous hydrochloric acid solution, as passed through indicated by IPC-6 (pH band).If meet IPC-6 standard, then the process of organic facies sodium bicarbonate aqueous solution is not less than 7 until Aqueous wash thing reaches pH, as passed through indicated by IPC-7 (pH band).Brief concentrated organic facies, adds fresh methylene chloride subsequently.Make organic solution pass silicagel pad, it then rinses by extra fresh methylene chloride to increase product recoveries.

The crystallization of unit operations 1.5:AP25047

Under reduced pressure concentrated methylene chloride solution, and use 2-propanol to replace dichloromethane by under reduced pressure azeotropic distillation to desired final volume scope.Then cool gained suspension, and under agitation make it aging further.

Unit operations 1.6: be separated/dry

The product of precipitation separation in agitation and filtration exsiccator under nitrogen flowing, and by 2-propanol flush cake.Under 45-55 DEG C (jacket temperature) under nitrogen current and decompression under agitation dry wet filter cake.Dry by IPC-8 (LOD, gravimetric analysis) monitoring.If meet IPC-8 standard, then product sampled and be packaged in Polythene Bag, and being placed on (expection productive rate scope 65-89%) in the coated aluminium foil bag of thermosealed mylar in HDPE conveying containers.

Step 2: synthesis AP24592 (" aniline ") intermediate

General introduction and synthesis flow

It is synthesize Aniline intermediates AP24592 by catalytic hydrogenation nitro-aromatic initial substance AP29089 that hydrochloric acid moors that step 2 for Buddhist nun's method, described as follows.React in the solvent ethyl acetate that initial substance and product height dissolve in wherein.Catalyst for this reaction is palladium/carbon, and is directly introduced in gaseous form in reactant mixture by hydrogen.When reaction completes, the solvent reached by distillation is exchanged into normal heptane from ethyl acetate and impels AP24592 spontaneous crystallization, thus generation has highly purified material.Show this crystallization and there is remarkable purification, because most of Process Impurity is still dissolved in normal heptane.

Controlling in 3 processes in step 2 is carry out HPLC to confirm initial substance consumption to reactant mixture, and after solvent azeotropic is exchanged into normal heptane, GC measures ethyl acetate, and solvent loss when weight analysis determining is dry.

flow process 3: step 1-step 2: synthesis AP24592

Unit operations 2.1: dissolve and hydrogen cleaning

AP29089,10% palladium/carbon and ethyl acetate are loaded in reactor, and stir suspension under Hydrogen Vapor Pressure.

Unit operations 2,2: hydrogenation

Reactor pressurized with hydrogen until reach steady pressure scope, and then stirs the mixture at least 4 hours under an atmosphere of hydrogen again.Reactor is reduced pressure, and obtains sample to assess reaction completeness (IPC-1).If meet IPC-1 standard, then process is made to proceed to unit operations 2.3

Unit operations 2.3: concentrated/crystallization

Make reactant mixture pass filter column casing to remove catalyst, and the extra ethyl acetate of column casing is washed.The concentrated filtrate that merges and wash solution are to remove the ethyl acetate of target volume under vacuo.Load normal heptane, and continue under vacuo to be distilled to target volume.Ethyl acetate content is measured by IPC-2 (GC).If meet IPC-2 standard, then process is made to proceed to unit operations 2.4.

Unit operations 2.4: be separated/dry

Dried solid product under vacuo under target temperature range.Dry end is determined by IPC-3 (LOD, gravimetric analysis).In the scope of 80-97% (based on AP29089 inlet amount), AP24592 is obtained to yellow solid form with white.

Step 3: synthesis moors that for Buddhist nun's free alkali

General introduction and synthesis flow

Step 3 synthesizes that free alkali for Buddhist nun of pool by base catalysis AP25047 and AP24592 reaction, and this is presented in flow process 4.Under highly basic, potassium tert-butoxide exist, under essentially no water condition, carry out reacting to make that the methyl ester of AP25047 is non-required is hydrolyzed into corresponding not reactive carboxylic acid and reduces to Min..The existence of this by-product not only causes loss of yield, and it is complicate downstream processing to cause during reaction treatment.Guarantee powerful reaction by being carried out dry reaction mixture by a series of azeotropic distillations of testing and control water in process and almost quantitatively consume initial substance.Based on DoE research, the parameter of the wherein reaction condition that repelled by brute force of Process Impurity and crystallization is fully understood.

flow process 4: step 3-synthesizes AP24534 free alkali

Unit operations 3.1: dry reaction mixture

AP25047, AP24592 and 2-methyltetrahydrofuran (2-Me-THF) is loaded in reactor.Under reduced pressure enriched mixture is to target volume.Add extra 2-methyltetrahydrofuran, and repeat distillation.After loading again 2-methyltetrahydrofuran and distillation circulation, in IPC-1 (KF), measure the water content of mixture.If meet IPC-1 standard, then process is made to proceed to unit operations 3.2.

Unit operations 3.2: reaction

Under the target temperature range of 13-23 DEG C, under agitation maintain suspension, load potassium tert-butoxide (KOtBu) simultaneously.After the period being no less than 3 hours, determine reaction progress by HPLC (IPC-2).If meet IPC standard, then process is made to proceed to unit operations 3.3.

Unit operations 3.3: cancellation and extraction

Reactant mixture 2-methyltetrahydrofuran (2-Me-THF) dilution, and by adding sodium-chloride water solution in addition cancellation.Be separated organic layer, and water layer 2-methyltetrahydrofuran extracting twice.The organic layer merged sequentially uses sodium-chloride water solution and water washing.Then at 15-30 DEG C, make organic layer aging.

Unit operations 3.4: concentrated/solvent exchange

After aging (see unit operations 3.3), make mixture pass column casing filter, and be concentrated into target volume under vacuo.Load 1-propanol, and make it at high temperature stir to provide solution, distill described solution under vacuo to target volume, then slowly cool to the temperature range of 20-30 DEG C.

Unit operations 3.5: crystallization

The solution age of product in 1-propanol is under agitation made until be visually observed and there is solid at the temperature of 20-30 DEG C.Under agitation acetonitrile is loaded in suspension, and at 20-30 DEG C, under agitation make gained suspension aging 60-120 minute again, be separated in next unit operation subsequently.

Unit operations 3.6: be separated/dry

The serosity produced in separation unit operation 3.5 in filter/dryer under vacuo.With the mixture of 1-propanol and acetonitrile by solids wash twice.Then drying solid under vacuo, and by IPC-3 (LOD, gravimetric analysis) monitoring.If meet IPC standard, then discharge the product in canescence to yellow solid, and be packaged in dual Polythene Bag to store at ambient temperature.

Step 4: synthetic hydrochloric acid moors that for Buddhist nun

General introduction and synthesis flow

Hydrochloric acid moor that for step 4 of Buddhist nun's method be pool by combining equimolar amounts in ethanol that for Buddhist nun's free alkali and hydrochloric acid, and form mono-hydrochloric salts by adding crystal seed induced crystallization.In DoE research, examine or check the parameter of this process to the impact producing solid form and particle size distribution needed for this process.The synthesis flow of step 4 is presented in flow process 5.

flow process 5: step 4-synthetic hydrochloric acid moors that for Buddhist nun

Unit operations 4.1: dissolve

AP24534 free alkali and dehydrated alcohol (EtOH) are loaded in reactor, and stirs to produce solution at 60-75 DEG C.Dissolving is verified by visualization.

Unit operations 4.2: clarification

Make solution pass filter, described filter then washs at 60-78 DEG C with ethanol.

Unit operations 4.3: acidify/add crystal seed

Enriched product solution is to target volume under vacuo.Under agitation, then the solution of the 1N hydrogen chloride of initial part (about 25%) in ethanol is loaded in reactor.At the temperature of 60-70 DEG C, use the brilliant Treatment Solution of qualified kind of hydrochloric acid AP24534 to cause crystallization.Process is made to proceed to unit operations 4.4.

Unit operations 4.4: crystallization

Once by there is solid in visualization confirmatory reaction device, the alcoholic solution namely slowly adding all the other (about 75%) 1N hydrogen chloride is in stirring the mixture.Make mixture ageing at least 10 minutes, and carry out IPC-1 to measure the pH of solution.If meet IPC standard, then the temperature of cooling mixture to 5-15 DEG C, and under agitation aging.

Unit operations 4.5: be separated/dry

By filtering separating solids product, and wash at the temperature of 5-15 DEG C with ethanol.By slowly stirring and flow of nitrogen gas remove excess ethyl alcohol from solid product at ambient temperature.Then drying solid under vacuo at 60-70 DEG C.Dry by IPC-2 (LOD, gravimetric analysis) monitoring.If meet IPC-2 standard, then discharge is moored that in canescence to the hydrochloric acid of yellow solid and is replaced Buddhist nun, and is packaged in dual Polythene Bag to store in plastic barrel at 20-30 DEG C.

Should be appreciated that being previously described in is exemplary and explanat in nature, and meant for illustration disclosed present general inventive concept and its preferred embodiment at present.By normal experiment, have benefited from of the present disclosurely one skilled in the art will recognize that the obvious modifications and variations do not departed under spirit and scope of the present disclosure.Therefore, the disclosure not by describing restriction above, but limits by following claim and their equivalent.

Claims

1. crystallization 3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl } benzamide hydrochloride salt.

2. substantially pure crystallization 3-according to claim 1 (imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl } benzamide hydrochloride salt.

3.3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl } crystal form A of benzamide monohydrochloride.

4. crystal form A as claimed in claim 3, wherein 3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl } the described crystal form A of benzamide monohydrochloride is substantially pure.

5. the crystal form A as described in claim 3 or 4, it comprises the characteristic peak x-ray powder diagram as shown in Figure 4 represented with the 2 θ number of degrees.

6. the crystal form A as described in claim 3 or 4, it comprises the characteristic peak that represents with the 2 θ number of degrees about 5.9; 7.1; 10.0; 12.5; 16.4; 19.3; 21.8; 23.8; With the x-ray powder diagram at 26.1 places.

7. the crystal form A as described in claim 3 or 4, it comprises the characteristic peak that represents with the 2 θ number of degrees about 5.9; 7.1; 10.0; 12.5; 13.6; 14.1; 15.0; 16.4; 17.7; 18.6; 19.3; 20.4; 21.8; 22.3; 23.8; 24.9; 26.1; 27.0; 28.4; 30.3; 31.7; With the x-ray powder diagram at 35.1 places.

8. the crystal form A according to any one of claim 3-7, wherein said substantially pure crystal form A is anhydrous.

9. the crystal form A according to any one of claim 3-7, wherein said substantially pure crystal form A is substantially free of ethanol in its crystallographic system.

10. crystal form A as claimed in claim 3, it has the onset melting temperature between about 262 DEG C to about 264 DEG C.

11. crystal form As claimed in claim 10, it has the onset melting temperature of about 264.1 DEG C.

12. crystal form As according to any one of claim 3-12, it comprises the FT-IR spectrum with arbitrary following frequency band:

Frequency (cm ^-1) 2938.1(2870-2960) 3242.1 2220.0 1669.8 1531.8 1314.9 1122.6 857.3，789.7

13. 1 kinds for the preparation of 3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl } method of crystal form A of benzamide monohydrochloride, it comprises makes 3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl } Benzoylamide contacts with hydrochloric acid.

14.3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl } crystal form B of benzamide monohydrochloride.

15. crystal form Bs as claimed in claim 14, wherein 3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl } the described crystal form B of benzamide monohydrochloride is substantially pure.

16. crystal form Bs as described in claims 14 or 15, it comprises the characteristic peak x-ray powder diagram as shown in Figure 15 represented with the 2 θ number of degrees.

17. crystal form Bs as described in claims 14 or 15, it comprises the characteristic peak that represents with the 2 θ number of degrees about 3.1; 6.5; 12.4; 13.8; 15.4; 16.2; 17.4; 18.0; 20.4; 23.2; 24.4; 26.1; With the x-ray powder diagram at 26.9 places.

18.3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl } the crystal form C of benzamide monohydrochloride.

19. crystal form C as claimed in claim 18, wherein 3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl } the described crystal form C of benzamide monohydrochloride is substantially pure.

20. crystal form C as described in claim 18 or 19, it comprises the characteristic peak x-ray powder diagram as shown in Figure 17 represented with the 2 θ number of degrees.

21. crystal form C as described in claim 18 or 19, it comprises the characteristic peak that represents with the 2 θ number of degrees about 3.1; 6.5; 12.4; 13.8; 17.4; 18.0; 20.6; 22.0; 23.0; 25.5; 26.5; 27.4; 28.4; With the x-ray powder diagram at 29.0 places.

22.3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl } the crystal form D of benzamide monohydrochloride.

23. crystal form D as claimed in claim 22, wherein 3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl } the described crystal form D of benzamide monohydrochloride is substantially pure.

24. crystal form D as described in claim 22 or 23, it comprises the characteristic peak x-ray powder diagram as shown in Figure 22 represented with the 2 θ number of degrees.

25. crystal form D as described in claim 22 or 23, it comprises the characteristic peak that represents with the 2 θ number of degrees about 8.2; 10.1; 10.9; 14.9; 16.0; 16.3; 16.8; 17.7; 18.7; 20.2; 22.9; 24.0; 25.6; 26.7; With the x-ray powder diagram at 28.5 places.

26.3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl } the crystal form E of benzamide monohydrochloride.

27. crystal form E as claimed in claim 26, wherein 3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl } the described crystal form E of benzamide monohydrochloride is substantially pure.

28.3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl } the crystal form F of benzamide monohydrochloride.

29. crystal form F as claimed in claim 28, wherein 3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl } the described crystal form F of benzamide monohydrochloride is substantially pure.

30. crystal form F as described in claim 28 or 29, it comprises the characteristic peak x-ray powder diagram as shown in Figure 27 represented with the 2 θ number of degrees.

31. crystal form F as described in claim 28 or 29, it comprises the characteristic peak that represents with the 2 θ number of degrees about 6.8; 9.8; 12.4; 16.2; 17.9; 19.0; 24.0; With the x-ray powder diagram at 25.1 places.

32.3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl } the crystal form G of benzamide monohydrochloride.

33. crystal form G as claimed in claim 32, wherein 3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl } the described crystal form G of benzamide monohydrochloride is substantially pure.

34.3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl } form H of benzamide monohydrochloride.

35. form Hs as claimed in claim 34, wherein 3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl } the described form H of benzamide monohydrochloride is substantially pure.

36. form Hs as described in claim 34 or 35, it comprises the characteristic peak x-ray powder diagram as shown in Figure 34 represented with the 2 θ number of degrees.

37. form Hs as described in claim 34 or 35, it comprises the characteristic peak that represents with the 2 θ number of degrees about 5.9; 8.1; 9.5; 10.7; 13.4; 16.0; 17.0; 22.0; 22.8; 24.7; With the x-ray powder diagram at 28.3 places.

38.3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl } crystalline form I of benzamide monohydrochloride.

39. crystalline form Is as claimed in claim 38, wherein 3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl } the described crystalline form I of benzamide monohydrochloride is substantially pure.

40.3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl } the crystal form J of benzamide monohydrochloride.

41. crystal form J as claimed in claim 40, wherein 3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl } the described crystal form J of benzamide monohydrochloride is substantially pure.

42. crystal form J as described in claim 40 or 41, it comprises the characteristic peak x-ray powder diagram as shown in Figure 43 represented with the 2 θ number of degrees.

43.3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl } the crystal form K of benzamide monohydrochloride.

44. crystal form K as claimed in claim 43, wherein 3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl } the described crystal form K of benzamide monohydrochloride is substantially pure.

45. crystal form K as described in claim 43 or 44, it comprises the characteristic peak x-ray powder diagram as shown in Figure 44 represented with the 2 θ number of degrees.

46. 1 kinds of pharmaceutical compositions, it comprises crystallization 3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl for the treatment of effective dose } benzamide monohydrochloride and pharmaceutically acceptable carrier, vehicle or excipient.

47. pharmaceutical compositions as claimed in claim 46, wherein said crystallization 3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl } benzamide monohydrochloride is substantially pure.

48. pharmaceutical compositions as described in claim 46 or 47, wherein said crystallization 3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl } benzamide monohydrochloride is the combination of crystal form A, crystal form B, crystal form C, crystal form D, crystal form E, crystal form F, crystal form G, form H, crystalline form I, crystal form J, crystal form K or any aforementioned forms.

49. pharmaceutical compositions as described in claim 46 or 47, wherein said crystallization 3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl } benzamide monohydrochloride is crystal form A.

50. 1 kinds of methods being used for the treatment of CML or Ph+ALL of experimenter in need, it comprises crystallization 3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl to described experimenter's administering therapeutic effective dose } benzamide monohydrochloride.

51. methods as claimed in claim 50, wherein said crystallization 3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl } benzamide monohydrochloride is substantially pure.

52. methods as described in claim 50 or 51, wherein said crystallization 3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl } benzamide monohydrochloride is the combination of crystal form A, crystal form B, crystal form C, crystal form D, crystal form E, crystal form F, crystal form G, form H, crystalline form I, crystal form J, crystal form K or any aforementioned forms.

53. methods as described in claim 50 or 51, wherein said crystallization 3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl } benzamide monohydrochloride is crystal form A.

54. crystallization 3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl } Benzoylamide.

55. substantially pure crystallization 3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl described in claim 54 } Benzoylamide.

56.3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl } crystal form A of Benzoylamide.

57. crystal form As claimed in claim 56, wherein 3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl } the described crystal form A of Benzoylamide is substantially pure.

58. crystal form As described in claim 56 or 57, it comprises the characteristic peak x-ray powder diagram as shown in Figure 51 represented with the 2 θ number of degrees.

59. crystal form As described in claim 56 or 57, it comprises the characteristic peak that represents with the 2 θ number of degrees about 6.2; 8.8; 9.9; 11.2; 12.3; 12.9; 13.5; 13.8; 14.2; 14.4; 16.0; 16.4; 17.2; 17.6; 18.0; 18.2; 19.3; 19.5; 19.8; 20.6; 21.5; 21.9; 22.2; 22.6; 23.1; 24.0; 24.4; 25.1; 25.6; 25.9; 26.8; 27.4; 27.8; 29.1; With the x-ray powder diagram at 29.8 places.

60. crystal form As described in claim 56 or 57, it comprises the characteristic peak that represents with the 2 θ number of degrees about 6.2; 12.3; 13.8; 14.4; 16.0; 16.4; 17.2; 17.6; 18.2; 19.5; 19.8; 20.6; 21.5; 22.2; 24.0; 25.9; 26.8; 27.4; With the x-ray powder diagram at 27.8 places.

61. crystal form As according to any one of claim 56-60, wherein said substantially pure crystal form A is anhydrate form.

62. crystal form As according to any one of claim 56-61, wherein said substantially pure crystal form A is substantially free of ethanol in its crystallographic system.

63. crystal form As claimed in claim 56, it has the onset melting temperature between about 199 DEG C to about 200 DEG C.

64. crystal form As described in claim 63, it has the onset melting temperature of about 199.6 DEG C.

65. crystal form As according to any one of claim 56-64, it comprises and having with cm ^-1the FT-IR spectrum of any one or combination of the following frequency band represented: 1605; 1415; 1295; 1250; 1150; 1145; 1110; 1100; 895; 855; With 790.

66.3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl } crystal form B of Benzoylamide.

67. crystal form Bs as described in claim 66, wherein 3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl } the described crystal form B of Benzoylamide is substantially pure.

68. crystal form Bs as described in claim 66 or 67, it comprises the characteristic peak x-ray powder diagram as shown in Figure 54 represented with the 2 θ number of degrees.

69. crystal form Bs according to any one of claim 66-68, it comprises the characteristic peak that represents with the 2 θ number of degrees about 5.6; 7.2; 9.8; 10.8; 12.1; 12.5; 12.8; 14.5; 15.3; 15.8; 17.0; 17.3; 17.5; 18.5; 19.0; 19.5; 20.0; 20.3; 21.1; 21.6; 22.4; 22.8; 23.5; 24.1; 24.5; 25.3; 26.0; 26.4; 27.0; 27.5; 28.4; 30.8; With the x-ray powder diagram at 32.0 places.

70. crystal form Bs as described in claim 66-69, it comprises the characteristic peak that represents with the 2 θ number of degrees about 5.6; 12.0; 14.0; 15.0; 15.5; 16.8; 18.1; 20.1; With the x-ray powder diagram at 26.0 places.

71.3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl } the crystal form C of Benzoylamide.

72. crystal form C as described in claim 71, wherein 3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl } the described crystal form C of Benzoylamide is substantially pure.

73. crystal form C as described in claim 71 or 72, it comprises the x-ray powder diagram of characteristic peak as shown in the top pattern in Figure 64 represented with the 2 θ number of degrees.

74. crystal form C according to any one of claim 71-73, it comprises the characteristic peak that represents with the 2 θ number of degrees about 3.2; 11.1; 11.7; 12.8; 13.3; 13.5; 14.2; 17.1; 18.2; 20.8; 22.3; With the x-ray powder diagram at 26.5 places..

75. crystal form C according to any one of claim 71-74, it comprises the characteristic peak that represents with the 2 θ number of degrees about 3.2; 12.8; 14.2; 17.1; 18.2; 20.8; The x-ray powder diagram at 22.3 and 26.5 places.

76.3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl } the crystal form D of Benzoylamide.

77. crystal form D as described in claim 76, wherein 3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl } the described crystal form D of Benzoylamide is substantially pure.

78. crystal form D as described in claim 76 or 77, it comprises the x-ray powder diagram of characteristic peak as shown in the middle pattern in Figure 67 represented with the 2 θ number of degrees.

79. crystal form D according to any one of claim 76-78, it comprises the characteristic peak that represents with the 2 θ number of degrees about 6.2; 8.0; 10.8; 11.5; 12.4; 13.5; 13.8; 14.5; 15.6; 16.5; 17.6; 18.5; 19.3; 19.8; 20.1; 20.8; 21.6; 22.1; 23.8; 26.0; 27.1; With the x-ray powder diagram at 29.6 places.

80. crystal form D according to any one of claim 76-79, it comprises the characteristic peak that represents with the 2 θ number of degrees about 6.2; 10.8; 12.4; 13.8; 14.5; 15.6; 16.5; 18.5; 20.2; 20.8; 21.6; 26.0; With the x-ray powder diagram at 27.1 places.

81.3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl } the crystal form E of Benzoylamide.

82. crystal form E as described in claim 81, wherein 3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl } the described crystal form E of Benzoylamide is substantially pure.

83. crystal form E as described in claim 81 or 82, it comprises the x-ray powder diagram of characteristic peak as shown in the top pattern in Figure 70 represented with the 2 θ number of degrees.

84. crystal form E as described in claim 83, it comprises the characteristic peak that represents with the 2 θ number of degrees about 6.2; 7.0; 10.0; 13.0; 15.1; 16.4; 17.2; 18.5; 20.4; 20.5; 22.5; 24.4; 25.6; With the x-ray powder diagram at 27.0 places.

85. crystal form E as described in claim 83 or 84, it comprises the characteristic peak that represents with the 2 θ number of degrees about 6.2; 7.0; 10.0; 15.1; 16.4; 17.2; 18.5; 20.4; 20.524.4; With the x-ray powder diagram at 27.0 places.

86. crystal form E as described in claim 81 or 82, it comprises the x-ray powder diagram of characteristic peak as shown in the middle pattern in Figure 70 represented with the 2 θ number of degrees.

87. crystal form E as described in claim 86, it comprises the characteristic peak that represents with the 2 θ number of degrees about 6.2; 7.0; 8.7; 9.8; 12.1; 12.5; 13.0; 15.2; 16.4; 17.2; 18.5; 20.0; 21.0; 23.0; 24.4; 25,0; With the x-ray powder diagram at 26.2 places.

88. crystal form E as described in claim 86 or 87, it comprises the characteristic peak that represents with the 2 θ number of degrees about 6.2; 7.0; 15.2; 16.4; 17.2; 18.5; 20.0; 21.0; 24.4; With the x-ray powder diagram at 26.2 places.

89.3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl } the crystal form F of Benzoylamide.

90. crystal form F as described in claim 89, wherein 3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl } the described crystal form F of Benzoylamide is substantially pure.

91. crystal form F as described in claim 89 or 90, it comprises the characteristic peak that represents with the 2 θ number of degrees x-ray powder diagram as shown in the 5th pattern started from top in Figure 83.

92. crystal form F according to any one of claim 89-91, it comprises the characteristic peak that represents with the 2 θ number of degrees about 7.2; 13.2; 14.1; 15.9; 18.1; 20.4; 21.1; 22.0; 23.5; 24.2; 25.5; With the x-ray powder diagram at 26.8 places.

93. crystal form F according to any one of claim 89-92, it comprises the characteristic peak that represents with the 2 θ number of degrees about 7.2; 13.2; 14.1; 15.9; 18.1; 20.4; 23.5; 25.5 and the x-ray powder diagram at 26.8 places.

94.3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl } the crystal form G of Benzoylamide.

95. crystal form G as described in claim 94, wherein 3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl } the described crystal form G of Benzoylamide is substantially pure.

96. crystal form G as described in claim 94 or 95, it comprises the characteristic peak that represents with the 2 θ number of degrees x-ray powder diagram as shown in the 4th pattern started from top in Figure 83.

97. crystal form G according to any one of claim 94-96, it comprises the characteristic peak that represents with the 2 θ number of degrees about 7.2; 13.2; 14.1; 15.9; 18.1; 20.4; 21.1; 22.0; 23.5; 24.2; 25.5; With the x-ray powder diagram at 26.8 places.

98. crystal form G according to any one of claim 94-97, it comprises the characteristic peak that represents with the 2 θ number of degrees about 5.0; 6.5; 9.5; 14.0; 15.0; 16.5; 17.2; 18.4; 20.0; With the x-ray powder diagram at 22.8 places.

99.3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl } form H of Benzoylamide.

100. the form H as described in claim 99, wherein 3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl } the described form H of Benzoylamide is substantially pure.

101. form Hs as described in claim 99 or 100, it comprises the x-ray powder diagram of characteristic peak as shown in any one in the Fig. 1-5 in Figure 74 represented with the 2 θ number of degrees.

102. form Hs according to any one of claim 99-101, it comprises the characteristic peak that represents with the 2 θ number of degrees about 6.2; 6.5; 10.1; 12.0; 13.2; 15.0; 15.5; 16.0; 16.5; 18.0; 19.1; 19.6; 20.5; 21.1; 23.0; 23.7; With the x-ray powder diagram at 25.5 places.

103. form Hs according to any one of claim 99-103, it comprises the characteristic peak that represents with the 2 θ number of degrees about 6.2; 12.0; 13.2; 16.0; 18.0; 19.1; 19.6; 20.5; 21.1; 23.0; With the x-ray powder diagram at 25.5 places.

104.3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl } crystalline form I of Benzoylamide.

105. the crystalline form I as described in claim 104, wherein 3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl } the described crystalline form I of Benzoylamide is substantially pure.

106. crystalline form Is as described in claim 104 or 105, it comprises the x-ray powder diagram of characteristic peak as shown in Figure 79 represented with the 2 θ number of degrees.

107. crystalline form Is according to any one of claim 104-106, it comprises the characteristic peak that represents with the 2 θ number of degrees about 6.5; 8.2; 9.8; 14.3; 15.5; 17.5; 21.2; 23.1; With the x-ray powder diagram at 26.5 places.

108. crystalline form Is according to any one of claim 104-107, it comprises the characteristic peak that represents with the 2 θ number of degrees about 6.5; 8.2; 9.8; 14.3; 15.5; 17.5; 21.2; With the x-ray powder diagram at 26.5 places.

109.3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl } the crystal form J of Benzoylamide.

110. crystal form J as described in claim 109, wherein 3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl } the described crystal form J of Benzoylamide is substantially pure.

111. crystal form J as described in claim 109 or 110, it comprises the x-ray powder diagram of characteristic peak as shown in the pattern 7 or 8 in Figure 80 represented with the 2 θ number of degrees.

112. crystal form J as described in claim 109 or 110, it comprises the characteristic peak that represents with the 2 θ number of degrees about 5.8; 7.0; 12.1; 15.1; 16.8; 18.1; 18.6; 19.1; 19.5; 20.1; 21.1; 21.8; 22.8; 25.0; 25.7; With the x-ray powder diagram at 27.0 places.

113. crystal form J as described in claim 109,110 or 112, it comprises the characteristic peak that represents with the 2 θ number of degrees about 5.8; 7.0; 12.1; 15.1; 16.8; 18.6; 19.1; 19.5; 21.8; 22.8; 25.0; 25.7; With the x-ray powder diagram at 27.0 places

114.3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl } the crystal form K of Benzoylamide.

115. crystal form K as described in claim 114, wherein 3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl } the described crystal form K of Benzoylamide is substantially pure.

116. crystal form K as described in claim 114 or 115, it comprises the characteristic peak that represents with the 2 θ number of degrees about 10.0; 11.0; 13.4; 14.6; 15.2; 16.0; 17.0; 17.5; 18.0; 19.6; 20.9; 22.1; 22.8; 24.1; 24.8; 26.5; 27.1; 28.5; With the x-ray powder diagram at 30.5 places.

117. crystal form K as described in claim 114-116, it comprises the characteristic peak that represents with the 2 θ number of degrees about 10.0; 11.0; 13-4; 14.6; 15.2; 16.0; 19.6; 20.9; 22.1; 22.8; 24.1; 24.8; With the x-ray powder diagram at 26.5 places.

118. one kinds of pharmaceutical compositions, it comprises crystallization 3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl for the treatment of effective dose } Benzoylamide and pharmaceutically acceptable carrier, vehicle or excipient.

119. the pharmaceutical composition as described in claim 118, wherein said crystallization 3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl } Benzoylamide is substantially pure.

120. pharmaceutical compositions as described in claim 118 or 119, wherein said crystallization 3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl } Benzoylamide is crystal form A, crystal form B, crystal form C, crystal form D, crystal form E, crystal form F, crystal form G, form H, crystalline form I, crystal form J, crystal form K or its any combination.

121. pharmaceutical compositions as described in claim 118 or 119, wherein said crystallization 3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl } Benzoylamide is crystal form A.

122. one kinds of methods being used for the treatment of CML or Ph+ALL of experimenter in need, it comprises crystallization 3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl to described experimenter's administering therapeutic effective dose } Benzoylamide.

123. methods as described in claim 122, wherein said crystallization 3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl } Benzoylamide is substantially pure.

124. methods as described in claim 122 or 123, wherein said crystallization 3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl } Benzoylamide is crystal form A, crystal form B, crystal form C, crystal form D, crystal form E, crystal form F, crystal form G, form H, crystalline form I, crystal form J, crystal form K or its any combination.

125. methods as described in claim 122 or 123, wherein said crystallization 3-(imidazo [1,2-b] pyridazine-3-ethyl-acetylene base)-4-methyl-N-{4-[(4-methylpiperazine-1-yl) methyl]-3-(trifluoromethyl) phenyl } benzamide monohydrochloride is crystal form A.